KR20200105837A - Compounds that can be used as tumor suppressors and their preparation and use - Google Patents

Abstract

(I)Compounds that can be used as tumor suppressors and their preparation and use. The compound has a structure represented by the general formula I, and includes stereoisomers, enantiomers, racemates, cis/trans isomers, tautomers, and isotopic variants thereof. The compounds can be used alone or in combination with other drugs for the treatment of tumors or inflammatory diseases, or other disorders or diseases mediated by MDM2 and/or MDM4 activity, and exhibit remarkable therapeutic activity.

(I)

Description

Compounds that can be used as tumor suppressors and their preparation and use

The present invention relates to the field of pharmaceutical preparations, and in particular, to compounds useful as tumor suppressors, and methods for their preparation and use.

P53 is a known tumor suppressor protein that plays an important role in the growth inhibition and apoptosis of tumor cells. P53 is a transcription factor that can control the response of cells to DNA damage and causes growth arrest, apoptosis, and aging. By preventing the proliferation of damaged cells (controlled cell death), the normal function of the cells can be maintained.

However, in about 50% of tumors, P53 is inactivated due to gene mutation or deletion, and in the remaining 50% of tumors, the function of P53 is a sequence in which MDM2 acts as a negative regulator of P53 and has an important regulatory action for the function of P53. Is regulated by a complex mechanism of In tumor cells, P53 is often inactivated due to overexpression of MDM2, and studies have found that MDM2 amplification or overexpression is present in about 10% of tumors, and in some specific tumors, the rate is higher, e.g. For example, about 44% of liver cancer, 20% of osteosarcoma, and 31% of soft tissue sarcoma have MDM2 amplification or overexpression. Therefore, inhibiting the negative regulatory action of MDM2 on P53 among tumor cells can activate the P53 pathway, and further inhibit the proliferation of tumor cells, thereby acting as an anti-tumor. Previously reported MDM2 inhibitors include RG7388, MI-773, HDM201, and the like.

RG7388 MI-773 HDM201

However, given the actual demand in the clinic, the development of other novel compounds that can be used as tumor suppressors is still urgent.

Accordingly, an object of the present invention is to overcome the deficiencies of the prior art, and to provide a compound that can be used as a tumor suppressor, and a method and use thereof.

A first aspect of the present invention is a compound of formula I; Or stereoisomers, enantiomers, diastereomers, racemates, mesomers, cis/trans isomers, tautomers, isotopic variants of the compounds of formula I, or any combination thereof; Or a pharmaceutical salt, solvate of the compound of Formula I, its stereoisomer, enantiomer, diastereomer, racemate, mesomer, cis/trans isomer, tautomer, isotopic variant, or any combination thereof , Hydrates, polymorphs or prodrugs; Or it provides a compound that is a hydrate of the pharmaceutical salt.

(I)

로부터 선택되며;Here, R ₁ is straight or branched chain alkyl or cycloalkyl having 1 to 5 carbon atoms, or

Is selected from;

R ₂ is selected from H, -(C ₁ -C ₆ alkyl), wherein the alkyl is optionally substituted with 0 to 3 substituents, wherein the 0 to 3 substituents independently have 1 to 4 carbon atoms. Alkoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or Selected from methanesulfonyl;

R ₃ is selected from unsubstituted or 5- or 6-membered aromatic rings or aromatic heterocycles substituted with 1 to 3 substituents, wherein 1 to 3 substituents are independently H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl, -O-(C ₃ -C ₆ )cycloalkyl, -S-(C ₁ -C ₆ )alkyl, halogen, halogenated Alkyl, halogenated alkoxy, hydroxyalkoxy, -CN, -C(O)NR ₉ R ₁₀ , -C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , methyl-imidazolyl-, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C( O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ ,- CH ₂ NR ₉ R ₁₀ , -C(O)O-(C ₁ -C ₄ )alkyl, -CH ₂ CN, tetrahydropyrrol-1-yl, azetidin-1-yl, or one or more -OH or Azetidin-1-yl substituted simultaneously with -CH ₃ and -OH; Here, the alkyl or cycloalkyl is optionally 0 to 3 independently having 1 to 4 carbon atoms alkoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or substituted with a substituent selected from methanesulfonyl; Preferably, R ₃ is selected from unsubstituted or 5- or 6-membered aromatic rings or aromatic heterocycles substituted with 1 to 3 substituents, wherein 1 to 3 substituents are independently H, (C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, halogen, halogenated alkyl, halogenated alkoxy, -CN, -C(O)NR ₉ R ₁₀ ,- C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , methyl-imida Zolyl-, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl,- N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)O-(C ₁ -C ₄ )alkyl, -CH ₂ CN, azetidin-1-yl, or azetidin-1-yl substituted simultaneously with one or more -OH or -CH ₃ and -OH; Here, the alkyl is optionally 0 to 3 independently alkoxy having 1 to 4 carbon atoms, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ ) substituted with a substituent selected from alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;

,

,

또는

로부터 선택되며; Or the R ₃ is

,

,

or

Is selected from;

R ₅ is selected from unsubstituted or 5- or 6-membered aromatic rings or aromatic heterocycles substituted with 1 to 3 substituents, wherein 1 to 3 substituents are independently H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl, -O-(C ₃ -C ₆ )cycloalkyl, -S-(C ₁ -C ₆ )alkyl, halogen, halogenated Alkyl, halogenated alkoxy, hydroxyalkoxy, -CN, -C(O)NR ₉ R ₁₀ , -C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , methyl-imidazolyl-, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C( O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ ,- CH ₂ NR ₉ R ₁₀ , -C(O)OCH ₃ , -CH ₂ CN, tetrahydropyrrol-1-yl, azetidin-1-yl, or at least one -OH or -CH ₃ and -OH simultaneously Selected from substituted azetidin-1-yl; Here, the alkyl or cycloalkyl is optionally 0 to 3 independently having 1 to 4 carbon atoms alkoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or substituted with a substituent selected from methanesulfonyl; Preferably, R ₅ is selected from unsubstituted or 5- or 6-membered aromatic rings or aromatic heterocycles substituted with 1 to 3 substituents, wherein 1 to 3 substituents are independently H, (C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, halogen, halogenated alkyl, halogenated alkoxy, -CN, -C(O)NR ₉ R ₁₀ ,- C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ CN , Methyl-imidazolyl-, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)OCH ₃ , -CH ₂ CN, azetidin-1-yl, or azetidin-1-yl substituted simultaneously with one or more -OH or -CH ₃ and -OH; Here, the alkyl is optionally 0 to 3 independently alkoxy having 1 to 4 carbon atoms, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ ) substituted with a substituent selected from alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;

,

,

,

,

,

,

또는

로부터 선택되며;Or the R ₅ is

,

,

,

,

,

,

or

Is selected from;

R ₆ is selected from halogen, methyl halide, methyl or cyano;

R ₇ is selected from H, (C ₁ -C ₆ )alkyl, or halogen; Here, the alkyl is optionally 0 to 3 independently alkoxy having 1 to 4 carbon atoms, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ ) substituted with a substituent selected from alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;

here,

R ₈ is selected from -OH, -OCH ₃ , -NH ₂ , -NHMe, -NMe ₂ , -NHCOMe, -NHCOH or methanesulfonyl;

R ₉ is selected from H or alkyl having 1 to 4 carbon atoms;

R ₁₀ is selected from H or (C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independently of 1 to 4 carbon atoms alkoxy, hydroxy, sulfhydryl, halogen, -C Substituted with a substituent selected from (O)OH, -C(O)O-(C ₁ -C ₄ )alkyl or methanesulfonyl;

R ₁₁ is selected from -OCH ₃ , -CH ₂ CH ₃ , -OH, methoxy halide or H;

R ₁₂ is selected from H or (C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independently of 1 to 4 carbon atoms alkoxy, hydroxy, sulfhydryl, halogen, -C Substituted with a substituent selected from (O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;

R ₁₃ is selected from halogen or alkyl having 1 to 4 carbon atoms;

R ₁₄ is selected from H or (C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independently of 1 to 4 carbon atoms alkoxy, hydroxy, sulfhydryl, halogen, -C Substituted with a substituent selected from (O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;

R ₁₅ is selected from NH ₂ , -C(O)OH, -NH(C(O)-CH ₃ ) or -C(O)-NH(CH ₃ );

R ₁₆ is selected from H, (C ₁ -C ₆ )alkyl or halogen; Here, the alkyl is optionally 0 to 3 independently alkoxy having 1 to 4 carbon atoms, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ ) substituted with a substituent selected from alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;

R ₁₇ is -C(O)-NR ₉ (R ₁₀ ), (C ₁ -C ₆ )alkyl, -C(O)(C ₁ -C ₆ )alkyl, -C(O)O(C ₁ -C ₆ ) is selected from alkyl; Here, the alkyl is optionally 0 to 3 independently alkoxy having 1 to 4 carbon atoms, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ ) substituted with a substituent selected from alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl; And/or

X ₁ is selected from oxygen or sulfur; Y, X ₂ , V and W are each independently selected from carbon or nitrogen; When Y is carbon, R ₄ is H, hydroxy, -O-(C ₁ -C ₆ )alkyl, -CN, halogen, -(C ₁ -C ₆ )alkyl, -C(O)OH, -CH ₂ C(O)OH, -CH ₂ C(O)NR ₉ R ₁₀ or -C(O)O-(C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independent Substituted with a substituent selected from alkoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl or methanesulfonyl having 1 to 4 carbon atoms do.

Preferably, the straight or branched chain alkyl or cycloalkyl having 1 to 5 carbon atoms in R ₁ is selected from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, cyclobutyl or cyclopentyl;

The alkoxy in R ₂ is selected from methoxy or ethoxy;

The alkyl halide in R ₃ is methyl halide, preferably -CF ₃ , -CHF ₂ or -CH ₂ F; Said halogenated alkoxy is _{-OCF 3, -OCHF 2, -OCH 2} F, -OCH 2 CF 3, -OCH 2 CHF 2 , or -OCH ₂ CH ₂ are selected from F, preferably -OCF _3, -OCHF _2, Or -OCH ₂ F; And/or the alkoxy is selected from methoxy or ethoxy;

The alkyl halide in R ₅ is methyl halide, preferably -CF ₃ , -CHF ₂ or -CH ₂ F; Said halogenated alkoxy is _{-OCF 3, -OCHF 2, -OCH 2} F, -OCH 2 CF 3, -OCH 2 CHF 2 , or -OCH ₂ CH ₂ are selected from F, preferably -OCF _3, -OCHF _2, Or -OCH ₂ F; And/or the alkoxy is selected from methoxy or ethoxy;

The halogen in R ₆ is selected from chlorine, fluorine or bromine, and/or the methyl halide is selected from trifluoromethyl, difluoromethyl or monofluoromethyl;

The alkoxy in R ₇ is selected from methoxy or ethoxy;

The alkyl in R ₉ is selected from methyl or ethyl;

The alkoxy in R ₁₀ is selected from methoxy or ethoxy;

The halogenated methoxyl in R ₁₁ is selected from -OCF ₃ , -OCHF ₂ or -OCH ₂ F;

The alkoxy in R ₁₂ is selected from methoxy or ethoxy;

The alkyl in R ₁₃ is selected from methyl or ethyl;

The alkoxy in R ₁₄ is selected from methoxy or ethoxy;

The alkoxy in R ₁₆ is selected from methoxy or ethoxy;

The alkoxy in R ₁₇ is selected from methoxy or ethoxy; And

The alkoxy in R ₄ is selected from methoxy or ethoxy.

In addition, in the compound of the present invention, preferably,

,

, 또는

이며;R ₁ is selected from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, cyclobutyl, cyclopentyl, or

,

, or

Is;

R ₂ is selected from H or methyl; Preferably H;

R ₃ is selected from a 6-membered aromatic ring or an aromatic heterocycle substituted with 1 to 3 substituents, and the substituents are independently H, -(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl, -O-(C ₃ -C ₆ )cycloalkyl, halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CH ₂ F, hydroxyalkoxy, -CN, -C(O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)O-(C ₁ -C ₄ )alkyl, -CH ₂ CN, tetrahydropyrrol-1-yl, wherein said alkyl or cycloalkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhi With a substituent selected from drill, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl Substituted; Preferably, R ₃ is selected from a 6-membered aromatic ring or an aromatic heterocycle substituted with 1 to 3 substituents, and the substituents are independently H, (C ₁ -C ₆ )alkyl, -O-(C _1- C ₆ )alkyl, halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -CN, -C(O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ CN, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)O-(C ₁ -C ₄ )alkyl, -CH ₂ CN, wherein the alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulf A substituent selected from hydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl Substituted with; Preferably, R ₃ is selected from 6-membered aromatic rings or aromatic heterocycles substituted with 1 to 3 substituents, and the substituents are independently H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy , ethoxy, isopropoxy, -O- cyclopropyl, hydroxy-ethoxy, _{halogen, -CF 3, -CHF 2, -CH} 2 F, -OCF 3, -OCHF 2, -OCH 2 F, -OCH 2 CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CH ₂ F, -CN, -C(O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ CN, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl , -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)O-(C ₁ -C ₄ ) Selected from alkyl, tetrahydropyrrol-1-yl;

R ₅ is selected from a 6-membered aromatic ring or an aromatic heterocycle substituted with 1 to 3 substituents, and the substituents are preferably independently H, -(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ ) Cycloalkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, -O-(C ₃ -C ₆ )cycloalkyl, halogen, -CF ₃ , -CHF ₂ , _{-CH 2 F, -OCF 3, -OCHF} 2, -OCH 2 F, -OCH 2 CF 3, -OCH 2 CHF 2, -OCH 2 CH 2 F, hydroxy-alkoxy, -CN, -C (O) NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O )OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)OCH ₃ , -CH ₂ CN, tetrahydropyrrol-1-yl, wherein the alkyl or cycloalkyl is optionally 0 to 3 independently methoxy, e Oxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or Substituted with a substituent selected from methanesulfonyl; Preferably, R ₅ is selected from a 6-membered aromatic ring or an aromatic heterocycle substituted with 1 to 3 substituents, and the substituents are preferably independently H, (C ₁ -C ₆ )alkyl, -O-( C ₁ -C ₆ )alkyl, halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -CN, -C(O)NR ₉ R ₁₀ ,- CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ CN, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O )OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)OCH ₃ , -CH ₂ CN, wherein the alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen, -C Substituted with a substituent selected from (O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl; Preferably, R ₅ is selected from a 6-membered aromatic ring or an aromatic heterocycle substituted with 1 to 3 substituents, and the substituents are independently H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy , ethoxy, isopropoxy, -O- cyclopropyl, hydroxy-ethoxy, _{halogen, -CF 3, -CHF 2, -CH} 2 F, -OCF 3, -OCHF 2, -OCH 2 F, -OCH 2 CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CH ₂ F, -CN, -C(O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ CN, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl , -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)OCH ₃ , tetrahydropyrrole-1- Is selected from work;

R ₆ is selected from chlorine or cyano; Preferably chlorine;

R ₇ is hydrogen;

X ₁ is oxygen; X ₂ , V and W are all carbon; And/or

Y is nitrogen or carbon; When Y is carbon, R ₄ is H, hydroxy, -O-(C ₁ -C ₆ )alkyl, -C(O)OH, -CH ₂ C(O)OH, -CH ₂ C(O)NR ₉ R ₁₀ or -C(O)O-(C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen , -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or substituted with a substituent selected from methanesulfonyl,

Wherein R ₉ is selected from H, methyl or ethyl;

R ₁₀ is selected from H or (C ₁ -C ₆ )alkyl, wherein said alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen, -C(O) Substituted with a substituent selected from OH, -C(O)O-(C ₁ -C ₄ )alkyl or methanesulfonyl.

Further, as a preferred embodiment of the present invention: when Y is nitrogen, R ₄ does not exist; When Y is carbon, R ₄ is H, hydroxy, -O-(C ₁ -C ₆ )alkyl, -C(O)OH, -CH ₂ C(O)OH, -CH ₂ C(O)NR ₉ R ₁₀ or -C(O)O-(C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen , -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;

R ₁ is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl;

R ₂ is H;

R ₃ is a 6-membered aromatic ring or an aromatic heterocycle substituted with 1 to 3 substituents, and the aromatic heterocycle is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring, wherein The substituents are independently H, -(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, -O- (C ₃ -C ₆₎ cycloalkyl, _{halogen, -CF 3, -CHF 2, -CH} 2 F, -OCF 3, -OCHF 2, -OCH 2 F, -OCH 2 CF 3, -OCH 2 CHF ₂ , -OCH ₂ CH ₂ F, hydroxyalkoxy, -CN, -C(O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -C (O)OH, -CH ₂ NR ₉ R ₁₀ , tetrahydropyrrol-1-yl or -NR ₉ R ₁₀ ; Here, the alkyl or cycloalkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ ) substituted with a substituent selected from alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl; Preferably, R ₃ is a 6-membered aromatic ring or aromatic hetero ring substituted with 1 to 3 substituents, and the aromatic hetero ring is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, or a pyridazine And the substituent is independently H, (C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, halogen, -CF ₃ ,- _{CHF 2, -CH 2 F, -OCF} 3, -OCHF 2, -OCH 2 F, -CN, -C (O) NR 9 R 10, -CH 2 NR 9 R 10, -CH 2 NR 9 -C ( O)R ₁₀ , -C(O)OH, -CH ₂ NR ₉ R ₁₀ , or -NR ₉ R ₁₀ ; Here, the alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl , -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or substituted with a substituent selected from methanesulfonyl; Preferably, R ₃ is selected from a 6-membered aromatic ring or an aromatic hetero ring substituted with 1 to 3 substituents, and the aromatic hetero ring is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, or Is a pyridazine ring, and the substituents are independently H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl, hydroxyethoxy, halogen,- _{CF 3, -CHF 2, -CH 2} F, -OCF 3, -OCHF 2, -OCH 2 F, -OCH 2 CF 3, -OCH 2 CHF 2, -OCH 2 CH 2 F, -CN, -C ( O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -C(O)OH, -CH ₂ NR ₉ R ₁₀ , tetrahydropyrrol-1-yl Or -NR ₉ R ₁₀ ;

R ₅ is a 6-membered aromatic ring or an aromatic hetero ring substituted with 1 to 3 substituents, and the aromatic hetero ring is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring; The substituents are independently H, -(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl , -O- (C ₃ -C ₆₎ cycloalkyl, _{halogen, -CF 3, -CHF 2, -CH} 2 F, -OCF 3, -OCHF 2, -OCH 2 F, -OCH 2 CF 3, -OCH ₂ CHF ₂ , -OCH ₂ CH ₂ F, hydroxyalkoxy, -CN, -C(O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ ,- C(O)OH, -CH ₂ NR ₉ R ₁₀ , tetrahydropyrrol-1-yl or -NR ₉ R ₁₀ ; Here, the alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl , -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or substituted with a substituent selected from methanesulfonyl; Preferably, R ₅ is a 6-membered aromatic ring or aromatic heterocycle substituted with 1 to 3 substituents, and the aromatic heterocycle is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring. Is; The substituents are independently H, (C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, halogen, -CF ₃ , -CHF ₂ , _{-CH 2 F, -OCF 3, -OCHF} 2, -OCH 2 F, -CN, -C (O) NR 9 R 10, -CH 2 NR 9 R 10, -CH 2 NR 9 -C (O) R ₁₀ , -C(O)OH, -CH ₂ NR ₉ R ₁₀ , or -NR ₉ R ₁₀ ; Here, the alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl , -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or substituted with a substituent selected from methanesulfonyl; Preferably, R ₅ is selected from a 6-membered aromatic ring or an aromatic hetero ring substituted with 1 to 3 substituents, and the aromatic hetero ring is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, or Is a pyridazine ring, and the substituents are independently H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl, hydroxyethoxy, halogen,- _{CF 3, -CHF 2, -CH 2} F, -OCF 3, -OCHF 2, -OCH 2 F, -OCH 2 CF 3, -OCH 2 CHF 2, -OCH 2 CH 2 F, -CN, -C ( O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -C(O)OH, -CH ₂ NR ₉ R ₁₀ , tetrahydropyrrol-1-yl Or -NR ₉ R ₁₀ ;

R ₆ is chlorine; R ₇ is hydrogen; X ₁ is oxygen; And/or X ₂ , V and W are all carbon;

Wherein R ₉ is selected from H, methyl or ethyl, R ₁₀ is selected from H, -(C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independently methoxy, ethoxy , Hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl or methanesulfonyl; R ₁₀ is preferably H, methyl, ethyl or 1-hydroxyethyl, more preferably H, methyl or ethyl.

Further, as the most preferred embodiment of the present invention:

R ₁ is selected from ethyl or isopropyl;

R ₂ is H;

R ₃ is a 6-membered aromatic ring or an aromatic hetero ring substituted with 1 to 3 substituents, and the aromatic hetero ring is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, and the substituent Is independently H, -(C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, halogen, -CF ₃ , -CHF ₂ ,- _{CH 2 F, -OCF 3, -OCHF} 2, -OCH 2 F, -CN, -C (O) NR 9 R 10, or -NR ₉ R ₁₀ is selected from;

When Y is nitrogen, R ₄ is absent;

R ₅ is a 6-membered aromatic ring or aromatic hetero ring substituted with 1 to 3 substituents, and the aromatic hetero ring is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, and the substituent Is independently H, -(C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, halogen, -CF ₃ , -CHF ₂ ,- _{CH 2 F, -OCF 3, -OCHF} 2, -OCH 2 F, -CN, or -C (O) is selected from NH _2;

R ₆ is chlorine; R ₇ is hydrogen;

X ₁ is oxygen; Y is nitrogen; X ₂ , V and W are all carbon;

Wherein R ₉ is selected from H, methyl or ethyl, and R ₁₀ is selected from H, methyl or ethyl.

More preferably, the compound according to the first aspect is one selected from the following structures:

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Depending on the type or combination of substituents, the compound represented by the general formula (I) of the present invention may have various isomers, for example, the isomers are stereoisomers (e.g.,'cis' and'trans' forms, Enantiomers), tautomers and optical isomers (eg, preferential and left-handed forms). In order to obtain a more ideal application activity, the compound of the present invention is preferably in the S configuration (S configuration). The compounds of the present invention include all of these isomers, and mixtures of these isomers mixed in any ratio, unless otherwise stated.

In addition, the present invention is a compound that is converted to Compound (I), which is an active ingredient of the pharmaceutical composition of the present invention, due to reactions induced by enzymes, gastric acid, etc. under physiological conditions in the body, that is, by enzyme oxidation, reduction, hydrolysis, etc. It also includes a compound that is converted to I), or a'pharmaceutically acceptable prodrug compound' that is converted to compound (I) by hydrolysis induced by gastric acid or the like.

Any structural formula provided herein also refers to the unlabeled and isotopically labeled forms of the compound. Isotope-labeled compounds or isotopic variants have structures represented by the structural formulas provided herein, except that one or more atoms have been replaced by an atom having a selected atomic mass or mass number. For example, the compound represented by the general formula (I) of the present invention may contain isotopes of non-natural proportions as one or more constituent atoms. Examples of isotopes include deuterium ⁽² H), tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) and the carbon -14 ⁽¹⁴ C), but is not limited to this. These compounds are useful therapeutic or prophylactic agents, research reagents (eg, test reagents) and diagnostic agents (eg, diagnostic contrast agents in the body). Regardless of the presence or absence of radioactivity, all isotopic variants of the compound represented by the general formula (I) are also included within the scope of the present invention.

The'pharmaceutically acceptable salt' of the present invention means an acid addition salt or a base addition salt of the compound of the present invention. 'Salt' includes in particular'pharmaceutical salt'. The term'pharmaceutical salt' refers to a salt that retains the biological effectiveness and properties of the compounds of the present invention, which is generally not biologically or other undesirable. In many cases, the compounds of the invention are capable of forming acidic and/or basic salts via the amino and/or carboxyl or similar groups present, e.g. pharmaceutical acid addition salts, for example with inorganic and organic acids. Acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, glucolate Heptanoate, gluconate, glucuronate, hippurate, hydroiodide/iodide, hydroxyethyl sulfonate, lactate, lactobionate, dodecyl sulfate, malate, maleate, malonate, mandelate , Mesylate, methyl sulfate, naphthalene formate, naphthalene sulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate , Propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.

Pharmaceutically solvates of the present invention, D ₂ O, d ₆ - include those which determine a solvent such as acetone, d ₆ -DMSO is be isotopically substituted.

In addition, the compounds of the present invention include salts thereof and may be obtained in the form of hydrates thereof, or may include other solvents for their crystallization. Because the compounds of the present invention are capable of forming solvates with pharmaceutical solvents (including water) either inherently or by design; This means that the present invention includes solvated and unsolvated forms. The term'solvate' refers to a molecular complex of a compound of the present invention (including a pharmaceutical salt thereof) and one or more solvent molecules. These solvent molecules are those commonly used in the pharmaceutical field, and are known to be harmless to receptors, such as water and ethanol. The term'hydrate' refers to a complex in which the solvent molecule is water. The compounds of the present invention include salts, hydrates and solvates thereof, and are capable of forming polymorphs either uniquely or by design. Solvates or hydrates can be used in the preparation of crystalline forms of compounds of formula (I).

A second aspect of the present invention provides a method for preparing a plurality of compounds of the first aspect as a preferred embodiment:

As a first parallel embodiment, when Y is N, the method of preparing the compound of formula I of the present invention comprises at least the following steps:

(1) synthesizing compound 3 by substituting and rearranging compound 1 and compound 2;

(2) cyclization reaction of compound 3 and compound 4 to form an imidazole ring to obtain compound 5;

(3) brominating compound 5 with NBS to obtain compound 6;

(4) obtaining compound 8 by performing low-temperature lithiation of compound 6 and compound 7 with LDA;

(5) ammonia decomposition reaction of compound 8 and compound 9 to obtain compound 10;

(6) acidifying and dehydrating compound 10 to obtain compound 11;

(7) obtaining a product 12 (corresponding to a compound represented by the general formula (I)) by reacting compound 11 with aryl or heteroaryl borate or boronic acid by Suzuki coupling;

Here, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , X ₁ , X ₂ , V, W are as defined in General Formula I.

In the above preparation method provided by the present invention, each step can be realized using various known reaction conditions, and as a preferred embodiment, the present invention further defines each step as follows:

In step 1, compound 2 is preferably added dropwise to compound 1 at 0±2° C., and reacted overnight at room temperature;

Step 2 preferably carries out the cyclization reaction at 70±2° C.;

Step 3 is preferably using tetrahydrofuran as a solvent, more preferably adding NBS several times at 0±2° C., followed by stirring at room temperature overnight;

Step 4 preferably uses tetrahydrofuran as a solvent, more preferably reacts at -78±2° C. for 2 hours;

Step 5 preferably uses toluene as a solvent, more preferably AlMe ₃ and compound 9 are added dropwise at 0±2°C, and reacted overnight at 90±2°C;

Step 6 preferably uses glacial acetic acid as a solvent and reacts at 110±5° C. for 2 hours under the action of concentrated sulfuric acid;

Step 7 is preferably 1,4-dioxane and water as a solvent, more preferably Pd(PPh ₃ ) ₄ as a catalyst, sodium carbonate or potassium phosphate as a base, 100±2° C. Microwave reaction was carried out for 1±0.5 hours at.

As a second parallel embodiment, when Y is C, the method of preparing the compound of formula I of the present invention comprises at least the following steps:

(1) synthesizing compound 3 by substitution reaction of compound 1 and compound 2;

(2) brominating compound 3 with NBS to obtain compound 4;

(3) obtaining compound 6 by lithiation of compound 4 and compound 5 with LDA at low temperature;

(4) obtaining compound 8 by subjecting compound 6 and compound 7 to ammonia decomposition reaction;

(5) acidifying and dehydrating compound 8 to obtain compound 9;

(6) obtaining a product 11 (corresponding to the compound represented by the general formula (I)) by reacting compound 9 with aryl or heteroaryl boronic acid by Suzuki coupling;

Here, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , X ₁ , X ₂ , V, W are as defined in General Formula I; Preferably X ₁ is O.

In the above preparation method provided by the present invention, each step can be realized using various known reaction conditions, and as a preferred embodiment, the present invention further defines each step as follows:

Here, step 1 preferably uses DMF as a solvent at 0±2° C., compound 2 is slowly added to compound 1, and reacted overnight at room temperature;

Step 2 is preferably using tetrahydrofuran as a solvent, adding NBS several times at 0±2° C., followed by stirring at room temperature overnight;

Step 3 is preferably using tetrahydrofuran as a solvent, and reacting at -78±2°C for 2±1 hours;

Step 4 preferably uses toluene as a solvent, adds AlMe ₃ and compound 7 dropwise at 0±2°C, and reacts overnight at 90±2°C;

Step 5 preferably uses glacial acetic acid as a solvent and reacts at 110±5° C. for 2±1 hours under the action of concentrated sulfuric acid;

Step 6 is preferably 1,4-dioxane and water as a solvent, Pd(PPh ₃ ) ₄ as a catalyst, sodium carbonate or potassium phosphate as a base, 1±0.5 at 100±5° C. Microwave reaction is carried out for hours.

The reaction of each step can be realized using conventional conditions in the art, and the present invention is not particularly limited thereto.

A third aspect of the present invention provides a pharmaceutical composition comprising at least one compound according to the first aspect as an active ingredient.

The compounds according to the first aspect of the invention can be advantageously combined with one or more therapeutically active agents, preferably with one or more other antiproliferative compounds. Such antiproliferative compounds include aromatase inhibitors; Antiestrogens; Topoisomerase I inhibitors; Topoisomerase II inhibitors; Microtubule active compounds; Alkylated compounds; Histone deacetylase inhibitors; Compounds that induce cell differentiation processes; Cyclooxygenase inhibitors; MMP inhibitors; MTOR inhibitors such as RAD001; Anti-tumor anti-metabolic substances; Platinum compounds; Compounds for targeting/reducing protein or lipid kinase activity; And additional anti-angiogenic compounds; Compounds for targeting, reducing or inhibiting protein or lipid phosphatase activity; Gonadorelin agonists; Anti-androgens; Methionine aminopeptidase inhibitors; Bisphosphonates; Biological response modifiers; Antiproliferative antibodies such as HCD122; Heparanase inhibitors; Inhibitors of Ras oncogenic isoforms; Telomerase inhibitors; Proteasome inhibitors; Compounds for treating blood cancer such as fludarabine; Compounds for targeting, reducing or inhibiting Flt-3 activity such as PKC412; 17-AAG (17-allylamino geldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics And Hsp90 inhibitors such as AUY922; Temozolomide (TEMODAL™); Kinesin spindle protein inhibitors such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; PI3K inhibitors such as BEZ235; RAF inhibitors such as RAF265; MEK inhibitors such as Array PioPharma's ARRY142886, AstraZeneca's AZD6244, Pfizer's PD181461, polynate calcium, EDG binding agents, anti-leukemia drug compounds, nucleotide reductase inhibitors, S-adenosylmethionine decarboxylase inhibitors, apoptosis regulators, antiproliferative Sex antibodies or other chemotherapeutic compounds. In addition, alternatively or additionally, they may be used in combination with other tumor treatment methods, these methods include surgical operations, ionizing radiation, photodynamic therapy, implants, for example corticosteroids, hormones, or these may be used as radiation sensitizers. I can. Also, in anti-inflammatory and/or anti-proliferative treatment, it includes a combination with anti-inflammatory agents. Combinations with antihistamines, bronchodilators, NSAIDs or chemokine receptor antagonists are also possible.

The pharmaceutical composition according to the present invention may further include a pharmaceutically acceptable carrier in addition to the active ingredient, and may be administered by various injections (for example, intravenous injections, intramuscular injections, and subcutaneous injections), or in various methods. It can be administered by (for example, oral administration and transdermal administration). The pharmaceutically acceptable carrier contains pharmaceutically acceptable materials (e.g., excipients, diluents, additives, solvents, etc.) for transporting the compound of the present invention or a composition containing the compound of the present invention from a specified organ to another organ it means.

Depending on the method of administration, a suitable formulation (for example, oral formulation or injection) may be selected, and a formulation may be prepared using various conventional formulation methods. Examples of oral preparations include tablets, powders, granules, capsules, pills, lozenges, solutions, syrups, elixirs, emulsions, oily or aqueous suspensions and the like.

In addition, the present invention provides a use of the compound according to the first aspect in the manufacture of a drug for the treatment of diseases based on cell cycle dysregulation.

In addition, there is provided a method for treating diseases related to MDM2 and P53 modulation, comprising administering to the patient an effective amount of a compound according to the first aspect of the present invention.

The compounds of the present invention are believed to be useful for the treatment of, for example, proliferative disorders or diseases based on cell cycle dysregulation, such as cancer or tumor diseases. In particular, these diseases or disorders are benign or malignant tumors, soft tissue sarcoma or liposarcoma, sarcoma such as rhabdomyosarcoma, or bone cancer such as osteosarcoma, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer. , Rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal or thyroid cancer, glioblastoma, meningioma, glioma, mesothelioma, multiple myeloma, gastrointestinal cancer, especially colon cancer or colorectal adenoma, head and neck tumor, melanoma, enlarged prostate, tumor formation, epithelial Characteristic tumor formation, leukemia such as acute myeloid leukemia or B-cell chronic lymphocytic leukemia, lymphoma such as lymphoma of B- or T-cell origin, and other organ metastasis, viral infections (e.g. herpes, papilloma, HIV, Kaposi's, viral hepatitis) and nephritis. Special uses include benign or malignant tumors, soft tissue sarcoma or liposarcoma, sarcoma such as rhabdomyosarcoma, or bone cancer such as osteosarcoma, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, Cancers such as pancreatic, lung, vaginal or thyroid cancer, mesothelioma, multiple myeloma, gastrointestinal cancer, especially colon or rectal adenoma, head and neck tumors, melanoma, enlarged prostate, tumor formation, epithelial tumor formation, acute myeloid leukemia or B- It is used in the treatment of leukemias such as cellular chronic lymphocytic leukemia, lymphomas such as lymphomas of B- or T-cell origin, and other organ metastasis and nephritis.

Preferably, it can be used for the treatment of leukemia, myeloma and nephritis.

In addition, the present invention is a method for treating a disease based on cell cycle dysregulation comprising administering an effective amount of a compound according to the first aspect or a composition according to the third aspect to a subject in need thereof by oral administration or parenteral administration route To provide;

The disease is preferably a tumor or nephritis disease; More preferably, it is a disorder or disease mediated by MDM2 and/or MDM4 activity.

In addition, the present invention is a method for treating a disease based on cell cycle dysregulation comprising administering an effective amount of a compound according to the first aspect or a composition according to the third aspect to a subject in need thereof by oral administration or parenteral administration route To provide;

Diseases based on the cell cycle dysregulation include cancer or tumor disease; The tumor diseases include benign or malignant tumors;

Preferably:

The tumor diseases include soft tissue sarcoma or sarcoma, leukemia or bone cancer; Preferably, the sarcoma is liposarcoma or rhabdomyosarcoma; The leukemia is acute myelogenous leukemia, chronic myelogenous leukemia or B-cell chronic lymphocytic leukemia; The bone cancer is osteosarcoma;

The cancer is brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer or thyroid cancer, glioblastoma, meningioma, glioma, mesothelioma, multiple myeloma, Including gastrointestinal cancer; In particular colon cancer or colorectal adenoma, head and neck tumor, melanoma, prostatic hyperplasia, tumorigenesis, tumorigenesis of epithelial features, leukemia, lymphoma, and other organ metastases and viral infections;

More preferably, the leukemia is acute myelogenous leukemia or B-cell chronic lymphocytic leukemia; The lymphoma is a lymphoma of B- or T-cell origin; The viral infection is herpes, papilloma, HIV, Kaposi's, viral hepatitis;

Alternatively, the disease based on the cell cycle regulation disorder is an immune system-related disorder or disease, preferably an autoimmune disease or immune disease, chronic inflammatory disease, or skin inflammatory or allergic disease, or other skin inflammatory or allergic disease due to transplantation. Disease, or hyperproliferative disorder;

Preferably:

The autoimmune diseases or immune diseases caused by the transplantation are rheumatoid arthritis, graft versus host disease, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, Hashimoto's thyroiditis, and multiple myositis;

The chronic inflammatory disease is asthma, osteoarthritis, nephritis, atherosclerosis or Morbus Crohn;

The skin inflammatory or allergic diseases include psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, polymorphic erythema, herpes dermatitis, sclerosis, vitiligo, allergic vasculitis, urticaria, vesicular pemphigus, pemphigus, acquired vesicular epidermis Detachment;

The hyperproliferative disorder is Li-Fraumeni syndrome.

In addition, the present invention provides a compound or composition for the treatment of diseases based on cell cycle dysregulation, wherein the compound is a compound according to the first aspect;

The disease is preferably a tumor or nephritis disease; More preferably, it is a disorder or disease mediated by MDM2 and/or MDM4 activity.

In addition, the present invention provides a compound or composition for the treatment of diseases based on cell cycle dysregulation, wherein the compound is a compound according to the first aspect;

Diseases based on the cell cycle dysregulation include cancer or tumor disease; The tumor diseases include benign or malignant tumors;

Preferably:

The tumor diseases include soft tissue sarcoma or sarcoma, leukemia or bone cancer; Preferably, the sarcoma is liposarcoma or rhabdomyosarcoma; The leukemia is acute myelogenous leukemia, chronic myelogenous leukemia or B-cell chronic lymphocytic leukemia; The bone cancer is osteosarcoma;

The cancer is brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer or thyroid cancer, glioblastoma, meningioma, glioma, mesothelioma, multiple myeloma, Including gastrointestinal cancer; In particular colon cancer or colorectal adenoma, head and neck tumor, melanoma, prostatic hyperplasia, tumorigenesis, tumorigenesis of epithelial features, leukemia, lymphoma, and other organ metastases and viral infections;

More preferably, the leukemia is acute myelogenous leukemia or B-cell chronic lymphocytic leukemia; The lymphoma is a lymphoma of B- or T-cell origin; The viral infection is herpes, papilloma, HIV, Kaposi's, viral hepatitis;

Alternatively, the disease based on the cell cycle regulation disorder is an immune system-related disorder or disease, preferably an autoimmune disease or immune disease, chronic inflammatory disease, or skin inflammatory or allergic disease, or other skin inflammatory or allergic disease due to transplantation. Disease, or hyperproliferative disorder;

Preferably:

The autoimmune diseases or immune diseases caused by the transplantation are rheumatoid arthritis, graft versus host disease, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, Hashimoto's thyroiditis, and multiple myositis;

The chronic inflammatory disease is asthma, osteoarthritis, nephritis, atherosclerosis or Morbus Crohn;

The skin inflammatory or allergic diseases include psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, polymorphic erythema, herpes dermatitis, sclerosis, vitiligo, allergic vasculitis, urticaria, vesicular pemphigus, pemphigus, acquired vesicular epidermis Detachment;

The hyperproliferative disorder is Li-Fraumeni syndrome.

When specifically applied, the dosage and the administration interval may be appropriately selected according to the location of the disease and the height, weight, sex, or medical history of the patient based on the judgment of the doctor. When administering the compound of the present invention to humans, the daily dose is about 0.01 to 500 mg/kg body weight, preferably about 0.1 to 100 mg/kg body weight. Preferably, the compound of the present invention may be administered to a person once a day, or the dosage may be divided into 2 to 4 times and repeatedly administered at appropriate time intervals. In addition, if necessary, the daily dosage may exceed the dosage according to the judgment of the doctor.

The following examples are intended to illustrate the present invention and are not intended to limit the scope of the present invention.

All raw materials used in the present invention are all known commercial products.

In the present invention,'Mdm2' refers to a protein encoded by a murine double minute 2 gene. 'Mdm2' includes the Mdm2 protein encoded by the full-length Mdm2 gene, the Mdm2 protein encoded by the mutated Mdm2 gene (including deletion mutants, substitution mutants and addition mutants), and the like. In the present invention,'Mdm2' also includes homologs derived from other animal species, such as human Mdm2 homolog (HDM2).

The abbreviations described in the examples of the present invention and their meanings are as follows:

NBS: N-bromosuccinimide

EA: ethyl acetate

PE: Petroleum ether

THF: tetrahydrofuran

LDA: lithium diisopropylamide

Pd(PPh ₃ ) ₄ : Tetrakis (triphenylphosphine) palladium

Example 1

6-chloro-5'-(3-chlorophenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3 ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

Step 1: Preparation of ethyl (E)-2-cyano-3-(dimethylamino)acrylate

Under a nitrogen gas atmosphere, ethyl 2-isocyanate (500.0 g, 4.425 mol) and 1000 mL of ethanol were added to a 2000 mL three-necked flask, cooled to -5°C, and 1,1-diethoxy-N-methyl-N-methylene methanamine (845.6 g, 5.752 mol) was added dropwise, and the temperature of the reaction solution was maintained at about 0°C during the dropwise addition process, and then the temperature was naturally raised to room temperature, stirred overnight, and concentrated in vacuo. The crude product was dissolved in 5 L of tert-butyl methyl ether, 1 Kg of silica gel was added, stirred for 30 minutes, filtered, washed 5 times with 500 mL of tert-butyl methyl ether, and concentrated in vacuo to ethyl (E). 678.2 g of -2-cyano-3-(dimethylamino)acrylate (yield 91.25%, yellow oily substance) was obtained. MS (ESI): mass calcd. for C ₈ H ₁₂ N ₂ O ₂ 168.2, m/z found 169.3 [M+H] ⁺ .

Step 2: Preparation of ethyl 1-isopropyl-1H-imidazole-4-carboxylate

In a nitrogen gas atmosphere, 500 ml of ethyl (E)-2-cyano-3-(dimethylamino) acrylate (120.0 g, 0.714 mol), n-butanol 100 ml, and propyl-2-amine (126.4 g, 2.14 mol) It was added to a three neck flask. The mixture was heated to 70° C. to react overnight, concentrated in vacuo, and 1000 mL of ethyl acetate was added, washed three times with 500 mL of saturated aqueous sodium chloride solution, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. , 119.3 g of ethyl 1-isopropyl-1H-imidazole-4-carboxylate (yield 91.76%, brown oily substance) was obtained. MS (ESI): mass calcd. For C ₉ H ₁₄ N ₂ O ₂ 182.2, m/z found 183.4 [M+H] ⁺ .

Step 3: Preparation of ethyl 2-bromo-1-isopropyl-1H-imidazole-4-carboxylate

In a nitrogen gas atmosphere, ethyl 1-isopropyl-1H-imidazole-4-carboxylate (60.0 g, 0.328 mol) and 500 mL of tetrahydrofuran were added to a 1000 mL 3-neck flask, cooled to 0°C, and NBS ( 87.0g, 0.492mol) was added in portions several times, naturally heated to room temperature, reacted overnight, concentrated in vacuo, 500 mL of ethyl acetate was added, and washed three times with 500 mL of saturated sodium carbonate aqueous solution, and then saturated sodium chloride Washed once with 45 mL of aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, separated by column chromatography (EA:PE=1:10-1:2), ethyl 2-bromo-1-isopropyl 21.2 g of -1H-imidazole-4-carboxylate (yield 24.7%, yellow oily substance) were obtained. MS (ESI): mass calcd. for C ₉ H ₁₃ BrN ₂ O ₂ 260.0, m/z found 261.5 [M+H] ⁺ .

Step 4: Preparation of ethyl 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-1-isopropyl-1H-imidazole-4-carboxylate

In a nitrogen gas atmosphere, ethyl 2-bromo-1-isopropyl-1H-imidazole-4-carboxylate (5.0 g, 19.15 mmol) and 10 mL of anhydrous THF were added to a 50 mL 3-neck flask, and the temperature was -78. After lowering to °C, LDA (40ml, 2M) was slowly added dropwise, maintained at -78 °C to react for 1.5 hours, and then 6-chlorodihydroindole-2,3-dione (3.46g, 19.15mmol) Anhydrous tetrahydrofuran solution (100ml) was slowly added dropwise, and after the dropwise addition was completed, the temperature was maintained at -78°C and reacted for 2 hours, then referred to as 100 ml of saturated ammonium chloride aqueous solution, and 200 ml of ethyl acetate was used. Extracted twice, combined the organic layers, washed once with 45 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and separated by column chromatography (EA:PE=1:10-1:2). Yellow solid ethyl 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-1-isopropyl-1H-imidazole-4-carboxylate (yield 17.0% , A yellow solid) 1.4 g was obtained. MS (ESI): mass calcd. for C ₁₇ H ₁₇ BrClN ₃ O ₄ 441.0, m/z found 442.0 [M+H] ⁺ .

Step 5: 2-Bromo-5-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-N-(3-chlorobenzene)-1-isopropyl-1H-imidazole-4 -Preparation of amide

In a nitrogen gas atmosphere, 3-chloroaniline (503.3mg, 2.94mmol) and 5 mL of anhydrous toluene were added to a 25 mL three-neck flask, the temperature was lowered to 0°C, and AlMe ₃ (1.2 mL, 25%w/w) was added to the reaction solution. ) Was slowly added dropwise, and then ethyl 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-1-isopropyl-1H-imidazole-4- Carboxylate (600mg, 1.36mmol) 5mL of anhydrous toluene solution was slowly added dropwise. The temperature was raised to 90°C and reacted overnight, and the temperature was naturally lowered to room temperature, 50 mL of ice water and 15 mL of saturated sodium potassium tartrate aqueous solution were added, and then extracted twice using 100 mL of dichloromethane each, and the organic layers were combined, and a saturated aqueous sodium chloride solution Washed once with 50 mL, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and separated by column chromatography, 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindole-3- Il)-N-(3-chlorobenzene)-1-isopropyl-1H-imidazol-4-amide (yield 56.47%, yellow solid) 401.2 mg was obtained. MS (ESI): mass calcd. for C ₂₁ H ₁₇ BrCl ₂ N ₄ O ₃ 522.0, m/z found 523.4 [M+H] ⁺ .

Step 6: 2'-bromo-6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'pyrrolo[3,4- d] Preparation of imidazole]-2,6'(5'H)-dione

2-Bromo-5-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-N-(3-chlorobenzene)-1-isopropyl-1H-imidazole-4-amide ( 400.0mg, 0.766mmol) and acetic acid (5mL) were added to a 25mL 3-neck flask, concentrated sulfuric acid (0.75g, 7.66mmol) was added in portions, and then the temperature was raised to 110°C and reacted overnight, and the temperature was naturally increased. After lowering to room temperature, 20 mL of ice water was added, the pH value was adjusted to 7.0 with a saturated aqueous sodium carbonate solution, extracted twice using 200 mL of dichloromethane, and the organic layers were combined, washed once with 50 mL of a saturated aqueous sodium chloride solution, and anhydrous sodium sulfate Dried over, filtered and concentrated in vacuo, separated by column chromatography (EA:PE=1:5-1:1), and 2'-bromo-6-chloro-5'-(3-chlorophenyl)- 3'-isopropyl-3'H-spiro[dihydroindole-3,4'pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (yield 33.67%, yellow) Solid) 130.2 mg was obtained. MS (ESI): mass calcd. for C ₂₁ H ₁₅ BrCl ₂ N ₄ O ₂ 504.0, m/z found 505.3 [M+H] ⁺ .

Step 7: 6-chloro-5'-(3-chlorophenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydro Preparation of indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

In a nitrogen gas atmosphere, in a microwave reaction flask 2'-bromo-6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (90.0mg, 0.178mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid ( 33.0mg, 0.178mmol), Pd(PPh ₃ ) ₄ (20.7mg, 0.0178mmol), anhydrous Na ₂ CO ₃ (57.0mg, 0.535mmol), 1,4-dioxane (4mL), water (1ml) added After that, the temperature was raised to 100° C. to perform a microwave reaction for 1 hour. The reaction solution was cooled to room temperature, filtered, water 10 mL was added, dichloromethane was extracted three times using 10 mL each, organic layers were combined, washed once with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and column Separated by chromatography, separated by supercritical high pressure preparative chromatography, (S)-6-chloro-5'-(3-chlorophenyl)-2'-(2,4-dimethoxypyrimidine-5- Il)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (S -1) 7.8 mg; (R)-6-chloro-5'-(3-chlorophenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-1) 8.8 mg was obtained. MS (ESI): mass calcd. for C ₂₇ H ₂₂ Cl ₂ N ₆ O ₄ 564.1, m/z found 565.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.54 (brs, 1H), 8.51 (s, 1H), 7.48 (d, 1H, J = 8.0Hz), 7.38-7.32 (m, 2H), 7.15- 7.12 (m, 2H), 7.01-6.97 (m, 1H), 6.96-6.95 (m, 1H), 4.19-4.12 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.12 ( d, 3H, J = 6.8 Hz), 0.64 (d, 3H, J = 6.8 Hz).

Example 2

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydro Indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2, 4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6 23.1mg of'(5'H)-dione (S-2); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H- 24.0 mg of spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-2) were obtained.

MS (ESI): mass calcd. for C ₂₈ H ₂₄ Cl ₂ N ₆ O ₄ 578.1, m/z found 579.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.62 (brs, 1H), 8.53 (m, 1H), 7.51-7.41 (m, 4H), 6.98-6.89 (m, 2H), 4.16-4.13 (m , 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.22 (s, 3H), 1.10 (d, 3H, J =4.8Hz), 0.67 (d, 3H, J =4.8Hz).

Example 3

6-chloro-5'-(3-chloro-4-fluorophenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(3-chloro-4-fluorophenyl)-2'-( 2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-3) 24.1mg, (R)-6-chloro-5'-(3-chloro-4-fluorophenyl)-2'-(2,4-di Methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5 35.8 mg of'H)-dione (R-3) was obtained. MS (ESI): mass calcd. for C ₂₇ H ₂₁ Cl ₂ FN ₆ O ₄ 582.1, m/z found 583.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.55 (brs, 1H), 8.51 (s, 1H), 7.51 (d, 1H, J =8.0Hz), 7.43-7.39 (m, 1H), 7.27 ( dd, 1H, J ¹ =9.2Hz, J ² =2.4Hz), 7.16-7.03 (m, 1H), 7.02-6.99 (m, 1H), 4.19-4.12 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.12 (d, 3H, J =6.8 Hz), 0.65 (d, 3H, J =6.8 Hz).

Example 4

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-fluoro-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3 ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4- Fluoro-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5 'H)-dione (S-4) 20.5 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-fluoro-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[di 22.3 mg of hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-4) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₃ Cl ₂ FN ₄ O ₃ 564.1, m/z found 565.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.47 (brs, 1H), 7.55-7.49 (m, 2H), 7.48-7.00 (m, 5H), 6.96-6.93 (m, 2H), 4.06-4.02 (m, 1H), 3.81 (s, 3H), 2.32 (s, 3H), 1.06 (d, 3H, J =5.2Hz), 0.63 (d, 3H, J =5.2Hz).

Example 5

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-methoxyphenyl)-3'H-spiro[dihydroindole-3,4'-pi Lolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(2-methoxyphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (S-5) 15.0 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-methoxyphenyl)-3'H-spiro[dihydroindole-3, 13.3 mg of 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-5) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₄ Cl ₂ N ₄ O ₃ 546.1, m/z found 547.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.52 (brs, 1H), 7.57-7.42 (m, 3H), 7.33-7.08 (m, 6H), 7.06-7.00 (m, 1H), 4.08-4.04 (m, 1H), 3.79 (s, 3H), 2.22 (s, 3H), 1.14 (d, 3H, J =5.2Hz), 0.64 (d, 3H, J =5.2Hz).

Example 6

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(5-fluoro-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3 ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(5- Fluoro-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5 'H)-dione (S-6) 17.0 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(5-fluoro-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[di 18.5 mg of hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-6) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₃ Cl ₂ FN ₄ O ₃ 564.1, m/z found 565.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.61 (brs, 1H), 7.54-7.00 (m, 8H), 6.97-6.96 (m, 1H), 4.07-4.04 (m, 1H), 3.78 (s , 3H), 2.49 (s, 3H), 1.08 (d, 3H, J =6.4 Hz), 0.65 (d, 3H, J =6.4 Hz).

Example 7

6-Chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-ethylphenyl)-3'-isopropylisopropyl-3'H-spiro[dihydroindole-3,4'- Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2- Ethylphenyl)-3'-isopropylisopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)- 26.3 mg of dione (S-7); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-ethylphenyl)-3'-isopropylisopropyl-3'H-spiro[dihydroindole-3 21.5 mg of ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-7) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₄ O ₂ 544.1, m/z found 545.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.70 (brs, 1H), 7.60-6.95 (m, 10H), 6.97-6.96 (m, 1H), 4.07-4.04 (m, 1H), 2.45 (s , 3H), 1.11-1.07 (m, 8H), 0.67 (d, 3H, J =4.8 Hz).

Example 8

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole- 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2, 6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'( 22.5 mg of 5'H)-dione (S-8); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[ 31.2 mg of dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-8) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₅ Cl ₂ N ₅ O ₄ 577.13, m/z found 578.2[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 7.82-7.80 (m, 1H), 7.79-7.04 (m, 6H), 6.56 (d, 2H, J =8.0Hz), 4.13-4.10 (m, 1H) ), 3.94 (s, 3H), 3.91 (s, 3H), 2.21 (s, 3H), 1.08 (d, 3H, J =6.4Hz), 0.66 (d, 3H, J =6.4Hz).

Example 9

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4' -Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2, 4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H) -19.5 mg of dione (S-9); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole- 18.3 mg of 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-9) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₄ O ₄ 576.1 m/z found 577.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.58 (brs, 1H), 7.55-6.67 (m, 9H), 4.08-4.04 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H) ), 2.20 (s, 3H), 1.06 (d, 3H, J =4.0Hz). 0.62 (d, 3H, J =4.0 Hz).

Example 10

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(3-methoxypyridin-4-yl)-3'H-spiro[dihydroindole-3, 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(3-methoxypyridin-4-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5' H)-dione (S-10) 25.8 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(3-methoxypyridin-4-yl)-3'H-spiro[dihydro 28.0 mg of indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-10) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₃ Cl ₂ N ₅ O ₃ 547.1, m/z found 548.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.79 (brs, 1H), 8.61 (s, 1H), 8.40 (d, 1H, J =4.8Hz), 7.62-7.45 (m, 2H), 7.33- 6.98 (m, 5H), 4.11-4.10 (m, 1H), 4.08 (s, 3H), 2.22 (s, 3H), 1.10 (d, 3H, J =6.8Hz), 0.66 (d, 3H, J = 6.8 Hz).

Example 11

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole- 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4, 6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'( 18.6mg 5'H)-dione (S-11); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[ 17.2 mg of dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-11) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₅ Cl ₂ N ₅ O ₄ 577.1, m/z found 578.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.61 (brs, 1H), 8.13 (d, 1H, J =4.8Hz), 7.55 (d, 1H, J =8.4Hz), 7.43-7.22 (m, 3H), 7.16-6.96 (m, 2H), 6.59 (d, 1H, J =1.6Hz), 4.10-4.04 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.22 (s , 3H), 1.08 (d, 3H, J =6.4Hz), 0.69 (d, 3H, J =6.4Hz).

Example 12

4-(6-Chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-3-methoxybenzonitrile

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-4-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'- Isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2' -Yl)-3-methoxybenzonitrile (S-12) 27.1 mg; (R)-4-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H 23.5 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-3-methoxybenzonitrile (R-12) were obtained. MS (ESI): mass calcd. for C ₂₇ H ₂₂ Cl ₂ N ₆ O ₄ 564.1, m/z found 565.3[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 7.73 (s, 1H), 7.68-7.62 (m, 1H), 7.60-7.46 (m, 2H), 7.16-7.09 (m, 2H), 7.01-6.97 (m, 2H), 4.06-4.03 (m, 1H), 3.87 (s, 3H), 2.22 (s, 3H), 1.07 (d, 3H, J =6.4Hz), 0.64 (d, 3H, J =6.4 Hz).

Example 13

3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxybenzonitrile

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'- Isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2' -Yl)-4-methoxybenzonitrile (S-13) 10.1 mg; (R)-3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H 13.7 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxybenzonitrile (R-13) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₃ Cl ₂ N ₅ O ₃ 571.1, m/z found 572.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.06-8.04 (m, 2H), 7.97-6.97 (m, 7H), 4.05-4.02 (m, 1H), 3.89 (s, 3H), 2.22 (s , 3H), 1.08 (d, 3H, J =6.4Hz), 0.65 (d, 3H, J =6.4Hz).

Example 14

6-chloro-5'-(3-chloro-2-fluorophenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chloro-2-fluorophenyl)-2'-( 2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-14) 54.9mg; (R)-6-chloro-5'-(3-chloro-2-fluorophenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3' 50.8 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-14) was obtained. MS (ESI): mass calcd. for C ₂₇ H ₂₁ Cl ₂ FN ₆ O ₄ 582.1, m/z found 583.5 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.52 (brs, 1H), 8.54 (s, 1H), 7.59 (t, 1H, J =6.8Hz), 7.34 (d, 1H, J =7.6Hz) , 7.23-7.14 (m, 2H), 7.03-6.98 (m, 2H), 4.20-4.13 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.12 (d, 3H, J = 6.8 Hz), 0.66 (d, 3H, J =6.8 Hz).

Example 15

6-chloro-5'-(5-chloro-2-ethylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-ethylphenyl)-2'-(2). ,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2, 17.5 mg of 6'(5'H)-dione (S-15); (R)-6-chloro-5'-(5-chloro-2-ethylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H 54.6 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-15) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₆ Cl ₂ N ₆ O ₄ 592.1, m/z found 593.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.38 (brs, 1H), 8.53 (d, 1H, J =6.8Hz), 7.58-7.09 (m, 5H), 7.07-6.95 (m, 1H), 4.17-4.14 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.57-2.48 (m, 2H), 1.14-1.02 (m, 6H), 0.67 (d, 3H, J =6.0 Hz).

Example 16

6-chloro-5'-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2'-(2,4-dimethoxypyrimidin-5-yl )-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-1-methyl-2-oxo-1,2 -Dihydropyridin-3-yl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'- 6.3 mg of pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (S-16); (R)-6-chloro-5'-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2'-(2,4-dimethoxypyrimidine -5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)- 8.1 mg of dione (R-16) was obtained. MS (ESI): mass calcd. for C ₂₆ H ₂₁ Cl ₂ N ₇ O ₅ 581.1, m/z found 582.1[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.30 (brs, 1H), 8.51 (s, 1H), 7.97 (d, 1H, J =2.4Hz), 7.31 (d, 1H, J =2.4), 7.21 (d, 1H, J =8.0), 7.04 (d, 1H, J =8.0), 6.99 (s, 1H), 4.13-4.08 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H ), 1.35 (s, 3H), 1.11 (d, 3H, J =6.8 Hz), 0.62 (d, 3H, J =8.0).

Example 17

6-chloro-5'-(5-chloro-2-methoxyphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-2-methoxyphenyl)-2'-( 2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-17) 15.1mg; (R)-6-chloro-5'-(5-chloro-2-methoxyphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3' 14.6 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-17) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₄ Cl ₂ N ₆ O ₅ 594.1, m/z found 595.2[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.49 (s, 1H), 7.30-7.28 (m, 1H), 7.10 (s, 1H), 7.43-7.22 (m, 3H), 7.98-6.96 (m , 2H), 6.75-6.74 (m, 2H), 4.08-4.03 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.63 (s, 3H), 1.12 (d, 3H, J =6.4Hz), 0.65 (d, 3H, J =6.4Hz).

Example 18

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxypyridin-3-yl)-3'H-spiro[dihydroindole-3, 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(4-methoxypyridin-3-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5' H)-dione (S-18) 23.7 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxypyridin-3-yl)-3'H-spiro[dihydro 30.9 mg of indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-18) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₃ Cl ₂ N ₅ O ₃ 547.1, m/z found 548.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.64 (d, 1H, J =5.6Hz), 8.50 (d, 1H, J =6.0Hz), 7.56-6.94 (m, 7H), 4.07-4.04 ( m, 1H), 3.89 (s, 3H), 2.20 (s, 3H), 1.09 (d, 3H, J =7.2Hz), 0.66 (d, 3H, J =7.2Hz).

Example 19

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-isopropyl-5-methoxyphenyl)-3'H-spiro[dihydroindole-3 ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(2-isopropyl-5-methoxyphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5 'H)-dione (S-19) 24.3 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-isopropyl-5-methoxyphenyl)-3'H-spiro[di 24.6 mg of hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-19) was obtained. MS (ESI): mass calcd. for C ₃₂ H ₃₀ Cl ₂ N ₄ O ₃ 588.2, m/z found 589.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ, 7.59-6.89 (m, 9H), 4.06-4.03 (m, 1H), 3.83 (s, 3H), 2.63-2.59 (m, 1H), 2.22 ( s, 3H), 1.23-1.15 (m, 6H), 0.83 (d, 3H, J =6.8 Hz), 0.65 (d.3H, J =6.8 Hz).

Example 20

6-chloro-5'-(3-chloro-4-methylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydro Indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(3-chloro-4-methylphenyl)-2'-(2, 4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6 24.0mg of'(5'H)-dione (S-20); (R)-6-chloro-5'-(3-chloro-4-methylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H- 27.9 mg of spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-20) were obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₄ Cl ₂ N ₆ O ₄ 578.1, m/z found 579.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.51 (s, 1H), 7.96 (brs, 1H), 7.94 (d, 1H, J =4.8Hz), 7.47 (d, 1H, J =8.0Hz) , 7.30 (d, 1H, J =8.0Hz), 7.15 (dd, 1H, J ¹ =8.0Hz, J ² =1.6Hz), 7.08-7.01(m, 1H), 6.87 (d, 1H, J =8.0 Hz), 4.18-4.13 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 2.26 (s, 3H), 1.11 (d, 3H, J =6.8Hz), 0.65 (d, 3H) , J =6.8 Hz).

Example 21

3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxy-N-methylbenzamide

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'- Isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2' -Yl)-4-methoxy-N-methylbenzamide (S-21) 26.4 mg; (R)-3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H -Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxy-N-methylbenzamide (R-21) 30.3 mg was obtained I did. MS (ESI): mass calcd. for C ₃₁ H ₂₇ Cl ₂ N ₅ O ₄ , 603.1 m/z found 604.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.46 (d, 1H, J = 4.0 Hz), 8.08-8.06 (m, 1H), 7.96 (s, 1H), 7.55 -6.99 (m, 6H), 4.08-4.04 (m, 1H), 3.86 (s, 3H), 2.77 (d, 3H, J = 4.0 Hz), 2.23 (s, 3H), 1.07 (d, 3H, J = 6.0 Hz), 0.65 (d , 3H, J = 6.0 Hz).

Example 22

3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxy-N,N-dimethylbenzamide

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'- Isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2' -Yl)-4-methoxy-N,N-dimethylbenzamide (S-22) 26.9 mg; (R)-3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H -Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxy-N,N-dimethylbenzamide (R-22) 29.5mg Was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₇ C _l2 N ₅ O ₄ , 617.1 m/z found 618.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 7.66-6.97 (m, 9H), 4.09-4.06 (m, 1H), 3.85 (s, 3H), 2.98 (s, 6H), 2.22 (s, 3H ), 1.08 (s, 3H), 0.65 (s, 3H).

Example 23

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-(dimethylamino)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4- (Dimethylamino)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6' 23.2mg (5'H)-dione (S-23); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-(dimethylamino)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro 22.3 mg of [dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-23) was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₉ Cl ₂ N ₅ O ₃ 589.2, m/z found 590.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.50 (brs, 1H), 7.51-6.38 (m, 9H), 4.12-4.09 (m, 1H), 3.77 (s, 3H), 3.00 (s, 6H) ), 2.22 (s, 3H), 1.06 (d, 3H, J =6.8 Hz), 0.62 (d, 3H, J =6.8 Hz).

Example 24

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-methoxy-4-methylphenyl)-3'H-spiro[dihydroindole-3,4 '-Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(2-methoxy-4-methylphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H )-Dione (S-24) 36.0mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-methoxy-4-methylphenyl)-3'H-spiro[dihydroindole 26.2 mg of -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-24) were obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₄ O ₃ 560.1, m/z found 561.1[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 7.54-6.91 (m, 9H), 4.08-4.04 (m, 1H), 3.77 (s, 3H), 2.39 (s, 3H), 2.22 (s, 3H) ), 1.06 (d, 3H, J =6.0Hz), 0.63 (d, 3H, J =6.0Hz).

Example 25

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-methoxy-4-(methylamine)phenyl)-3'H-spiro[dihydroindole -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(2-methoxy-4-(methylamine)phenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (S-25) 9.0 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-methoxy-4-(methylamine)phenyl)-3'H-spiro 11.6mg of [dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-25) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₇ Cl ₂ N ₅ O ₃ 575.2, m/z found 576.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.69 (brs, 1H), 7.55-6.22 (m, 9H), 4.13-4.09 (m, 1H), 3.72 (s, 3H), 2.74 (s,3H) ), 2.22 (s, 3H) 1.05 (d, 3H, J =5.2Hz), 0.60 (d, 3H, J =5.2Hz).

Example 26

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-ethyl-3'H-spiro[dihydroindole -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2, 4-dimethoxypyrimidin-5-yl)-3'-ethyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6' 26.2mg (5'H)-dione (S-26); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-ethyl-3'H-spiro 28.3 mg of [dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-26) was obtained. MS (ESI): mass calcd. for C ₂₇ H ₂₂ Cl ₂ N ₆ O ₄ 564.1, m/z found 565.1[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.54 (d, 1H, J =6.0Hz), 7.64-6.95 (m, 6H), 3.99 (s, 3H), 3.95 (s, 3H), 3.58- 3.50 (m, 1H), 2.25 (s, 3H), 1.17 (d, 3H, J =6.0Hz), 0.85 (d, 3H, J =6.0Hz).

Example 27

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxypyrimidin-5-yl)-3'H-spiro[dihydroindole-3 ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(4-methoxypyrimidin-5-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5 'H)-dione (S-27) 2.2 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxypyrimidin-5-yl)-3'H-spiro[di 3.6 mg of hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-27) was obtained. MS (ESI): mass calcd. for C ₂₇ H ₂₂ Cl ₂ N ₆ O ₃ 548.1, m/z found 549.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.19 (brs, 1H), 8.99 (s, 1H), 8.76 (d, 1H, J =7.2Hz), 7.57-6.98 (m, 6H), 4.19- 4.12 (m, 1H), 4.00 (s, 3H), 2.22 (s, 3H), 1.11 (d, 3H, J =6.8Hz), 0.68 (d, 3H, J =6.8Hz).

Example 28

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-cyclopropane-2'-(2,4-dimethoxypyrimidin-5-yl)-3'H-spiro[dihydro Indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-cyclopropane- 2'-(2,4-dimethoxypyrimidin-5-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6 10.2 mg of'(5'H)-dione (S-28); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-cyclopropane-2'-(2,4-dimethoxypyrimidin-5-yl)-3'H- 11.0 mg of spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-28) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₂ Cl ₂ N ₆ O ₄ 576.1, m/z found 577.1[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.58 (brs, 1H), 8.55 (d, 1H, J =4.0Hz), 7.56-6.97 (m, 6H), 3.99 (s, 3H), 3.96 ( s, 3H), 3.01-3.00 (m, 1H), 2.23 (s, 3H), 0.85-0.47 (m, 4H).

Example 29

3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxybenzamide

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'- Isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2' 6.1 mg of -yl)-4-methoxybenzamide (S-29); (R)-3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H 6.6 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxybenzamide (R-29) were obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₅ Cl ₂ N ₅ O ₄ 589.1, m/z found 590.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.08 (d, 1H, J =6.8Hz), 7.98 (brs, 2H), 7.37-6.52 (m, 8H), 4.02-3.96 (m, 1H), 3.84 (s, 3H), 2.26 (s, 3H), 1.10 (d, 3H, J =7.2Hz), 0.66 (d, 3H, J =7.2Hz).

Example 30

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-(difluoromethoxy)phenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3, 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2- (Difluoromethoxy)phenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5' H)-dione (S-30) 36.0 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-(difluoromethoxy)phenyl)-3'-isopropyl-3'H-spiro[dihydro 36.8 mg of indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-30) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₂ Cl ₂ F ₂ N ₄ O ₃ 582.1, m/z found 583.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.55 (brs, 1H), 7.69-6.96 (m, 10H), 4.08-4.07 (m, 1H), 2.22 (s, 3H), 1.08 (d, 3H) , J =6.0Hz), 0.67 (d, 3H, J =6.4Hz).

Example 31

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-(trifluoromethoxy)phenyl)-3'H-spiro[dihydroindole-3, 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(2-(trifluoromethoxy)phenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5' H)-dione (S-31) 19.9 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-(trifluoromethoxy)phenyl)-3'H-spiro[dihydro 18.9 mg of indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-31) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₁ Cl ₂ F ₃ N ₄ O ₃ 600.1, m/z found 601.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.54 (brs, 1H), 7.77-6.96 (m, 10H), 4.10-4.03 (m, 1H), 2.22 (s, 3H), 1.09 (d, 3H) , J =7.2Hz), 0.70 (d, 3H, J =6.4Hz).

Example 32

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-isopropyl-2-methoxyphenyl)-3'H-spiro[dihydroindole-3 ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(4-isopropyl-2-methoxyphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5 27.7 mg of'H)-dione (S-32); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-isopropyl-2-methoxyphenyl)-3'H-spiro[di 33.9 mg of hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-32) was obtained. MS (ESI): mass calcd. for C ₃₂ H ₃₀ Cl ₂ N ₄ O ₃ 588.2, m/z found 589.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.71 (brs, 1H), 7.56-6.48 (m, 9H), 4.08-4.05 (m, 1H), 3.79 (s, 3H), 3.01-2.94 (m) , 1H), 2.22 (s, 3H) 1.27-1.23 (m, 6H), 1.07 (d, 3H, J =6.8 Hz), 0.63 (d, 3H, J =6.8 Hz).

Example 33

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-ethyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3, 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4- Ethyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5' H)-dione (S-33) 21.8 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-ethyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydro 20.5 mg of indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-33) was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₈ Cl ₂ N ₄ O ₃ 574.2, m/z found 575.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.70 (brs, 1H), 7.55-6.50 (m, 9H), 4.08-4.04 (m, 1H), 3.78 (s, 3H), 2.72-2.50 (m , 2H), 2.22 (s, 3H), 1.27-1.06 (m, 3H), 1.06 (d, 3H, J =6.4 Hz), 0.63 (d, 3H, J =6.4 Hz).

Example 34

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-isopropoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'- Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2- Isopropoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)- 18.8 mg of dione (S-34); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-isopropoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3 21.1 mg of ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-34) was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₈ Cl ₂ N ₄ O ₃ 574.2, m/z found 575.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.67 (brs, 1H), 7.54-6.95 (m, 10H), 4.65-4.62 (m, 1H), 4.12-4.08 (m, 1H), 2.22 (s , 3H), 1.18 (m, 6H), 1.07 (d, 3H, J =7.2 Hz), 0.65 (d, 3H, J =6.4 Hz).

Example 35

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-ethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pi Lolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2- Ethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (S-35) 15.9 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-ethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3, 23.0 mg of 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-35) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₄ O ₃ 560.1, m/z found 561.5 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.68 (brs, 1H), 7.55-6.95 (m, 10H), 4.09-4.08 (m, 3H), 2.22 (s, 3H), 1.24 (t, 3H) , J =6.0Hz), 1.07 (d, 3H, J =6.8Hz), 0.65 (d, 3H, J =6.8Hz).

Example 36

6-chloro-5'-(3-chlorophenyl)-2'-(2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo [3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(2,4-dime. Toxiphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione ( S-36) 29.1 mg; (R)-6-chloro-5'-(3-chlorophenyl)-2'-(2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4 36.6 mg of'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-36) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₄ C _l2 N ₄ O ₄ 562.1, m/z found 563.1[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ7.47-7.45 (m, 1H), 7.38-7.36 (m, 3H), 7.13-7.12 (m, 2H), 7.02 (s, 1H), 6.97 ( d, 1H, J =7.2Hz), 6.72-6.67 (m, 2H), 4.11-4.00 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 1.10 (d, 3H, J = 5.2Hz), 0.60 (d, 3H, J =5.2Hz).

Example 37

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(5-ethyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3, 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(5- Ethyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5' H)-dione (S-37) 21.5 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(5-ethyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydro 32.4 mg of indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-37) was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₈ Cl ₂ N ₄ O ₃ 574.1, m/z found 575.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 7.70-6.98 (m, 9H), 4.08-4.05 (m, 1H), 3.76 (s, 3H), 2.64-2.60 (m, 2H), 2.22 (s , 3H), 1.23-1.17 (m, 3H), 1.07 (d, 3H, J =5.2 Hz), 0.63 (d, 3H, J =5.2 Hz).

Example 38

6-chloro-5'-(3-chlorophenyl)-2'-(5-ethyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'- Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(5-ethyl-2. -Methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)- 18.1 mg of dione (S-38); (R)-6-chloro-5'-(3-chlorophenyl)-2'-(5-ethyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3 23.1 mg of ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-38) were obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₄ O ₃ 560.1, m/z found 561.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.52 (brs, 1H), 7.48 (d, 1H, J =8.0Hz), 7.39-7.32 (m, 3H), 7.15-7.10 (m, 3H), 7.01 (s, 1H), 6.98-6.96 (d, 1H, J =7.2Hz), 4.10-4.04 (m, 1H), 3.75 (s, 3H), 2.64 (q, 2H, J =7.2Hz), 1.24 (t, 3H, J =7.2Hz), 1.10 (d, 3H, J =5.2Hz), 0.61 (d, 3H, J =5.2Hz).

Example 39

6-chloro-5'-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2'-(2,4-dimethoxyphenyl)-3'-iso Propyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-1-methyl-2-oxo-1,2 -Dihydropyridin-3-yl)-2'-(2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4 -d]imidazole]-2,6'(5'H)-dione (S-39) 8.0 mg; (R)-6-chloro-5'-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2'-(2,4-dimethoxyphenyl)- 3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-39) 12.7 mg was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₄ C _l2 N ₄ O ₄ 593.1, m/z found 594.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.44 (brs, 1H), 7.96 (d, 1H, J =2.4Hz), 7.33-7.31 (m, 2H), 7.22 (d, 1H, J = 8.0 Hz), 7.04 (d, 1H, J = 8.0Hz), 6.98 (s, 1H), 6.70-6.66 (m, 2H), 4.07-4.01 (m, 1H), 3.84 (s, 3H), 3.77 (s , 3H), 2.98 (m, 1H), 1.08 (d, 3H, J =6.4Hz), 0.58 (d, 3H, J =6.4Hz).

Example 40

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,5-dimethoxypyridin-4-yl)-3'-isopropyl-3'H-spiro[dihydroindole- 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2, 5-dimethoxypyridin-4-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'( 20.2 mg of 5'H)-dione (S-40); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,5-dimethoxypyridin-4-yl)-3'-isopropyl-3'H-spiro[ 28.2 mg of dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-40) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₅ Cl ₂ N ₅ O ₄ 577.1, m/z found 578.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.62 (brs, 1H), 8.10 (s, 1H), 7.56-6.95 (m, 7H), 4.11-4.10 (m, 1H), 3.86 (s, 3H) ), 3.83 (s, 3H), 2.21 (s, 3H), 1.10 (d, 3H, J =6.4Hz), 0.66 (d, 3H, J =6.4Hz).

Example 41

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-cyclobutyl-2'-(2,4-dimethoxypyrimidin-5-yl)-3'H-spiro[dihydro Indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-cyclobutyl- 2'-(2,4-dimethoxypyrimidin-5-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6 23.5 mg of'(5'H)-dione (S-41); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-cyclobutyl-2'-(2,4-dimethoxypyrimidin-5-yl)-3'H- 23.3 mg of spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-41) were obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₄ Cl ₂ N ₆ O ₄ 590.1, m/z found 591.1 [M+H] ⁺ . ¹ H-NMR (300MHz, DMSO- d ₆ ) δ 11.38 (brs, 1H), 8.49 (d, 1H, J =5.4Hz), 7.56-7.47 (m, 1H), 7.45-6.45 (m, 5H), 4.47-4.43 (m, 1H), 3.98-3.94 (m, 6H), 2.21 (s, 3H), 2.01-1.71 (m, 3H), 1.61-1.31 (m, 2H), 1.30-1.29 (m, 1H) ).

Example 42

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H -Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole ]-2,6'(5'H)-dione (S-42) 8.3mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl 8.9 mg of -3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-42) was obtained. . MS (ESI): mass calcd. for C ₂₇ H ₂₃ Cl ₂ N ₇ O ₄ 579.1, m/z found 580.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.53-8.46 (m, 2H), 7.61-6.96 (m, 4H), 4.17-4.13 (m, 1H), 3.98 (s, 3H), 3.94 (s , 3H), 2.40 (s, 1H), 0.84 (d, 3H, J =6.8 Hz), 0.66 (d, 3H, J =6.8 Hz).

Example 43

6-Chloro-5'-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3'-isopropyl-2'-(2-methoxyphenyl)- 3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-1-methyl-2-oxo-1,2 -Dihydropyridin-3-yl)-3'-isopropyl-2'-(2-methoxyphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d ]Imidazole]-2,6'(5'H)-dione (S-43) 26.2mg; (R)-6-chloro-5'-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3'-isopropyl-2'-(2-me Toxoxyphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-43) 28.2mg Was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₃ Cl ₂ N ₅ O ₄ 563.1, m/z found 564.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 7.95 (d, 1H, J = 2.4Hz), 7.56 (t, 1H, J =7.2Hz), 7.41 (d, 1H, J = 7.2Hz), 7.31 (d, 1H, J = 2.4Hz), 7.23-7.08 (m, 3H), 6.93 (s, 1H), 4.04-4.01 (m, 1H), 3.98 (s, 3H), 1.10 (d, 3H, J = 5.4Hz), 0.60 (d, 3H, J = 5.4Hz).

Example 44

6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-( 2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-44) 15.4mg; (R)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3' 19.7 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-44) was obtained. MS (ESI): mass calcd. for C ₂₇ H ₂₁ Cl ₂ FN ₆ O ₄ 582.1, m/z found 583.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.53 (s, 1H), 7.48-7.47 (m, 1H), 7.46-7.36 (m, 2H), 7.21-7.11 (m, 1H), 7.10-7.06 (m, 1H),7.05-7.01 (m, 1H), 4.20-4.15 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.17 (d, 3H, J =6.8Hz), 0.66 (d, 3H, J =6.8 Hz).

Example 45

6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-( 2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-45) 28.1mg; (R)-6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3' 29.8 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-45) was obtained. MS (ESI): mass calcd. for C ₂₇ H ₂₁ Cl ₂ FN ₆ O ₄ 582.1, m/z found 583.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.51 (s, 1H), 7.49-7.39 (m, 2H), 7.38-7.14 (m, 2H), 7.07-6.85 (m, 2H), 4.19-4.14 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.12 (d, 3H, J =6.8 Hz), 0.64 (d, 3H, J =6.8 Hz).

Example 46

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-cyclopropyl-2'-(2,4-dimethoxypyrimidin-5-yl)-3'H-spiro[dihydro Indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-cyclopropyl- 2'-(2,4-dimethoxypyrimidin-5-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6 5.0 mg of'(5'H)-dione (S-46); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-cyclopropyl-2'-(2,4-dimethoxypyrimidin-5-yl)-3'H- 10.5 mg of spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-46) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₆ O ₄ , 604.1 m/z found 605.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.51 (d, 1H, J = 6.8Hz), 7.50-6.48 (m, 7H), 4.32-4.27 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.21 (s, 3H), 1.92-1.91 (m, 1H), 1.69-1.67 (m, 1H), 1.37-1.23 (m, 4H), 0.91-0.80 (m, 2H).

Example 47

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-((dimethylamino)methyl)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4- ((Dimethylamino)methyl)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-47) 9.7mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-((dimethylamino)methyl)-2-methoxyphenyl)-3'-isopropyl-3' 9.4 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-47) were obtained. MS (ESI): mass calcd. for C ₃₂ H ₃₁ Cl ₂ N ₅ O ₃ 603.2, m/z found 604.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ7.42-6.73 (m, 9H), 4.07-3.98 (m, 1H), 3.77 (s, 3H), 2.14 (s, 6H), 2.08 (s, 2H), 1.08 (d, 3H, J =6.8 Hz), 0.63 (d, 3H, J =6.8 Hz).

Example 48

6-chloro-5'-(3-chloro-4-methoxyphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chloro-4-methoxyphenyl)-2'-( 2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-48) 32.4mg; (R)-6-chloro-5'-(3-chloro-4-methoxyphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3' 34.4 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-48) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₄ Cl ₂ N ₆ O ₅ 594.1, m/z found 595.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.57 (brs, 1H), 8.51 (s, 1H), 7.48 (d, 1H, J =8.0Hz), 7.14-7.07 (m, 3H), 6.97- 6.92 (m, 2H), 4.16-4.11 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 3.81 (s, 3H), 1.11 (d, 3H, J =6.4Hz), 0.65 (d, 3H, J =6.4 Hz).

Example 49

2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3, 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-( 5-Chloro-2-methylphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5' 5.4 mg of H)-dione (S-49); (R)-2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H-spiro[dihydro 17.1 mg of indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-49) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₅ Cl ₂ N ₅ O ₃ , 561.1 m/z found 562.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 7.44-7.15 (m, 4H), 7.02-6.85 (m, 3H), 6.30 (s, 1H), 6.25 (d, 1H, J = 8.0 Hz), 5.55 (brs, 2H), 4.24-4.06 (m, 1H), 3.67 (s, 3H), 2.22 (s, 3H), 1.06 (d, 1H, J = 6.4 Hz), 0.61 (d, 1H, J = 6.4 Hz).

Example 50

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-1'-isopropyl-1'H-spiro[dihydro Indole-3,6'-pyrrolo[3,4-b]pyrrole]-2,4'(5'H)-dione

Step 1: Preparation of methyl 1-isopropyl-1H-pyrrole-3-carboxylate

In a nitrogen gas atmosphere, methyl 1H-pyrrole-3-carboxylate (25 g, 0.1998 mol) and 30 ml of anhydrous tetrahydrofuran were added to a 500 mL 3-neck flask, cooled to 0° C., and NaH (7.19 g, 0.2997 mol). Was added in portions several times, and reacted for 30 minutes while maintaining the temperature, and 2-bromopropane (49.2g, 0.3996mol) was slowly added dropwise, and the temperature was naturally raised to room temperature and reacted overnight. The temperature was lowered to 0°C, 20 mL of water was added dropwise to quench, concentrated under reduced pressure, 500 mL of ethyl acetate was added, washed three times with 500 mL of saturated sodium carbonate aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. And, separated by column chromatography (EA:PE=20%~25%), methyl 1-isopropyl-1H-pyrrole-3-carboxylate (yield 63.2%, yellow oily substance) 21.1g was obtained. I did. MS (ESI): mass calcd. for C ₉ H ₁₃ NO ₂ 167.1, m/z found 168.2 [M+H] ⁺ .

Step 2: Preparation of methyl 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylate

In a nitrogen gas atmosphere, methyl 1-isopropyl-1H-pyrrole-3-carboxylate (5.0 g, 0.02994 mol) and 30 mL of anhydrous tetrahydrofuran were added to a 100 mL 3-neck flask, cooled to 0°C, and NBS ( 5.06g, 0.0284mol) was added in portions several times, naturally heated to room temperature and reacted overnight, concentrated in vacuo, and 50 mL of ethyl acetate was added, followed by washing three times with 50 mL of saturated sodium carbonate aqueous solution. Dried over sodium sulfate, separated by column chromatography (EA:PE=5%~25%), methyl 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylate (yield 93%, yellow oil Form material) 5.8 g were obtained. MS (ESI): mass calcd. for C ₉ H ₁₂ BrNO ₂ 245.0, m/z found 246.1 [M+H] ⁺ .

Step 3: Preparation of methyl 5-bromo-2-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-1-isopropyl-1H-pyrrole-3-carboxylate

In a nitrogen gas atmosphere, methyl 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylate (4.8 g, 0.0196 mol) and 20 mL of anhydrous tetrahydrofuran were added to a 100 mL 3-neck flask, and the temperature was- It was lowered to 78℃, LDA (39.2ml, 2M) was slowly added dropwise, and after the dropwise addition was completed, the temperature was maintained at -50℃ and reacted for 1.5 hours, and then 6-chloroindoline-2,3-dione (3.546g , 19.6 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, slowly added dropwise to the reaction flask, and reacted for 1 hour by maintaining the temperature at -50°C. 10 mL of saturated aqueous ammonium chloride solution was added dropwise to the reaction flask, concentrated in vacuo, 100 mL of ethyl acetate was added, washed once with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, followed by column chromatography (EA: PE=1:10~1:2) and methyl 5-bromo-2-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-1-isopropyl-1H-pyrrole 1.2 g of -3-carboxylate (yield 20%, yellow solid) was obtained. MS (ESI): mass calcd. for C ₁₇ H ₁₆ BrClN ₂ O ₄ 426.0, m/z found 409.0 [M+H-18] ⁺ .

Step 4: 5-Bromo-N-(5-chloro-2-methylphenyl)-2-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-1-isopropyl-1H- Preparation of pyrrole-3-amide

In a nitrogen gas atmosphere, 5-chloro-2-methylaniline (450mg, 3.169mmol) and anhydrous toluene (5mL) were added to a 50mL reaction flask, and the temperature was lowered to 0°C, and AlMe ₃ (1.826g, 25%w/ w) was slowly added, then methyl 5-bromo-2-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-1-isopropyl-1H-pyrrole-3-carboxylate (675mg, 1.585mmol) was dissolved in 5 mL of toluene and slowly added dropwise to the reaction flask, the temperature was raised to 90°C and reacted overnight, the temperature was lowered to room temperature, 20 mL of ice water and 15 mL of saturated sodium potassium tartrate aqueous solution were added, followed by dichloromethane. Was extracted twice using 50 mL each, and the organic phases were combined, washed once with 30 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, and separated into a preparative plate, and 5-bromo-N-(5 -Chloro-2-methylphenyl)-2-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-1-isopropyl-1H-pyrrol-3-amide (yield 94%, yellow solid ) 795 mg was obtained. MS (ESI): mass calcd. for C ₂₃ H ₂₀ BrCl ₂ N ₃ O ₃ 535.0, m/z found 518.0 [M+H-18] ⁺ .

Step 5: 2'-bromo-6-chloro-5'-(5-chloro-2-methylphenyl)-1'-isopropyl-1'H-spiro[dihydroindole-3,6'-pyrrolo[ Preparation of 3,4-b]pyrrole]-2,4'(5'H)-dione

To a 50 mL reaction flask 5-bromo-N-(5-chloro-2-methylphenyl)-2-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-1-isopropyl-1H -Pyrrol-3-amide (1155mg, 2.155mmol), H ₂ SO ₄ (2.112g, 21.55mmol), and acetic acid (10mL) were added, the temperature was raised to 110°C and reacted overnight, the temperature was lowered to room temperature, and ice water 20 mL was added, the pH value was adjusted to about 7 with a saturated aqueous sodium carbonate solution, extracted twice with 50 mL of dichloromethane, and the organic layers were combined, washed once with 20 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. And concentrated, and separated by column chromatography (EA:PE = 25%), 2'-bromo-6-chloro-5'-(5-chloro-2-methylphenyl)-1'-isopropyl-1' 150 mg of H-spiro[dihydroindole-3,6'-pyrrolo[3,4-b]pyrrole]-2,4'(5'H)-dione (yield 13.5%, yellow solid) was obtained. MS (ESI): mass calcd. for C ₂₃ H ₁₈ BrCl ₂ N ₃ O ₂ 517.0, m/z found 518.0 [M+H] ⁺ .

Step 6: 6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-1'-isopropyl-1'H-spiro Preparation of [dihydroindole-3,6'-pyrrolo[3,4-b]pyrrole]-2,4'(5'H)-dione

In a nitrogen gas atmosphere, in a microwave reaction flask, 2'-bromo-6-chloro-5'-(5-chloro-2-methylphenyl)-1'-isopropyl-1'H-spiro[dihydroindole-3 ,6'-pyrrolo[3,4-b]pyrrole]-2,4'(5'H)-dione (100mg, 0.1934mmol), (2,4-dimethoxypyrimidin-5-yl) boron After adding acid (36mg, 0.1934mmol), Pd(PPh ₃ ) ₄ (45mg, 0.0387mmol), Na ₂ CO ₃ (62mg, 0.5802mmol), dioxane (4mL) and H ₂ O (1ml), 100 The temperature was raised to °C and microwave reaction was performed for 1 hour. Cooled to room temperature and filtered, 10 mL of water was added, extracted three times using 10 mL of dichloromethane, and the organic layers were combined, washed once with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, Separated with a preparative plate, separated by supercritical high pressure preparative chromatography, (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxypyrimidine -5-yl)-1'-isopropyl-1'H-spiro[dihydroindole-3,6'-pyrrolo[3,4-b]pyrrole]-2,4'(5'H)-dione (S-50) 6.2 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-1'-isopropyl-1'H- 7.8 mg of spiro[dihydroindole-3,6'-pyrrolo[3,4-b]pyrrole]-2,4'(5'H)-dione (R-50) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₅ C _l2 N ₅ O ₄ 577.1, m/z found 578.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 9.51 (d, 1H, J = 8.0Hz), 7.62-6.55 (m, 8H), 4.07 (s, 3H), 3.94 (s, 3H), 3.62- 3.48 (m, 1H), 2.25 (s, 3H), 1.29 (d, 3H, J = 6.4Hz), 1.09 (d, 3H, J = 6.4Hz).

Example 51

6-chloro-5'-(3-chloro-5-methylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydro Indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

Following similar steps as in Example 1 to obtain the title compound, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(3-chloro-5-methylphenyl)-2'-(2, 4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6 18.9mg of'(5'H)-dione (S-51); (R)-6-chloro-5'-(3-chloro-5-methylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H- 18.4 mg of spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-51) was obtained. MS (ESI): mass calcd. for: C ₂₈ H ₂₄ Cl ₂ N ₆ O ₄ , 579.4 m/z found 580.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.60 (brs, 1H), 8.51 (s, 1H), 7.46 (d, 1H, J =8.0Hz), 7.18-7.13 (m, 2H), 7.02 ( s, 1H), 6.89 (s, 1H), 6.80 (s, 1H), 4.18-4.11 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 2.20 (s, 3H),1.12 (d, 3H, J =6.8 Hz), 0.64 (d, 3H, J =6.8 Hz).

Example 52

6-chloro-5'-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2'-(2,4-dimethoxyphenyl)-3'-iso Propyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-1-methyl-6-oxo-1,6 -Dihydropyridin-3-yl)-2'-(2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4 -d]imidazole]-2,6'(5'H)-dione (S-52) 17.2mg; (R)-6-chloro-5'-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2'-(2,4-dimethoxyphenyl)- 3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-52) 14.7 mg was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₅ Cl ₂ N ₅ O ₅ 593.1, m/z found 594.3[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.51 (s, 1H), 7.55-7.51 (m, 2H), 7.49-7.27 (m, 2H), 7.18-7.14 (m, 1H), 7.02 (s , 1H), 6.71-6.66 (m, 2H), 4.07-4.02 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.32 (s, 3H), 1.07 (d, 3H, J =6.8 Hz), 0.62 (d, 3H, J =6.8 Hz).

Example 53

6-chloro-5'-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3'-isopropyl-2'-(2-methoxyphenyl)- 3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-1-methyl-6-oxo-1,6 -Dihydropyridin-3-yl)-3'-isopropyl-2'-(2-methoxyphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d ]Imidazole]-2,6'(5'H)-dione (S-53) 18.3mg; (R)-6-chloro-5'-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3'-isopropyl-2'-(2-me Toxoxyphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-53) 18.2mg Was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₃ Cl ₂ N ₅ O ₄ 564.1, m/z found 565.3[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.49 (brs, 1H), 7.57-7.52 (m, 3H), 7.52-7.48 (m, 2H), 7.21-7.19 (m, 2H), 7.16-7.12 (m, 1H), 7.10-7.02 (m, 1H), 4.07-4.02 (m, 1H), 3.78 (s, 3H), 3.49 (s, 3H), 1.08 (d, 3H, J =6.8Hz), 0.62 (d, 3H, J =6.8 Hz).

Example 54

4-(6-Chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-3-methoxy-N-methylbenzamide

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-4-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'- Isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2' 7.5 mg of -yl)-3-methoxy-N-methylbenzamide (S-54); (R)-4-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H -Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-3-methoxy-N-methylbenzamide (R-54) 8.8 mg was obtained I did. MS (ESI): mass calcd. for C ₃₁ H ₂₇ Cl ₂ N ₅ O ₄ , 603.1 m/z found 604.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.59 (d, 1H, J = 4.4 Hz), 7.59-6.94 (m, 9H), 4.08-4.04 (m, 1H), 3.85 (s, 3H), 2.83 (d, 3H, J = 4.4 Hz), 2.23 (s, 3H), 1.08 (d, 3H, J = 5.2 Hz). 0.64 (d, 3H, J = 5.2 Hz).

Example 55

6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-5'-(m-tolyl)-3'H-spiro[dihydroindole-3, 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)- 3'-isopropyl-5'-(m-tolyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5' H)-dione (S-55) 52.7mg; (R)-6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-5'-(m-tolyl)-3'H-spiro[dihydro 58.7 mg of indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-55) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₅ ClN ₆ O ₄ 544.2, m/z found 545.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.51 (s, 1H), 7.42 (d, 1H, J =8.0Hz), 7.20-6.99 (m, 3H), 6.96 (s, 1H), 6.84 ( s, 1H), 6.97 (d, 1H, J =8.0Hz), 4.18-4.11 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.20 (s, 3H), 1.10 (d , 3H, J =6.8 Hz), 0.65 (d, 3H, J =6.8 Hz).

Example 56

6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)-5'-(2,5-dimethylphenyl)-3'-isopropyl-3'H-spiro[dihydroindole -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)- 5'-(2,5-dimethylphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (S-56) 42.4 mg; (R)-6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)-5'-(2,5-dimethylphenyl)-3'-isopropyl-3'H-spiro 48.7 mg of [dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-56) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₇ ClN ₆ O ₄ 558.1, m/z found 559.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.54 (brs, 1H), 8.54 (d, 1H, J =7.6Hz), 7.62-7.37 (m, 1H), 7.25-7.23 (m, 1H), 7.06-6.93 (m, 4H), 4.16-4.13 (m, 1H), 3.99 (s, 3H), 3.96 (s, 3H), 2.22 (s, 3H), 2.03 (s, 3H), 1.09 (d, 3H, J =6.8 Hz), 0.64 (d, 3H, J =6.8 Hz).

Example 57

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-fluoro-6-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3 ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2- Fluoro-6-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5 'H)-dione (S-57) 19.9 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-fluoro-6-methoxyphenyl)-3'-isopropyl-3'H-spiro[di 17.9 mg of hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-57) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₃ Cl ₂ FN ₄ O ₃ 564.1, m/z found 565.1[M+H] ⁺ . ¹ H-NMR (300MHz, DMSO- d ₆ ) δ 11.12 (brs, 1H), 7.62-6.97 (m, 9H), 4.01-3.98 (m, 1H), 3.82 (s, 3H), 2.23 (s, 3H) ), 1.07-1.02 (m, 3H), 0.70-0.63 (m, 3H).

Example 58

6-chloro-5'-(3-chloro-5-methoxyphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

Following similar steps as in Example 1 to obtain the title compound, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(3-chloro-5-methoxyphenyl)-2'-( 2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-58) 26.3mg; (R)-6-chloro-5'-(3-chloro-5-methoxyphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3' 29.9 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-58) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₄ Cl ₂ N ₆ O ₅ 594.1, m/z found 595.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.65 (brs, 1H), 8.51 (s, 1H), 7.47 (d, 1H, J = 8.4Hz), 7.16 (d, 1H, J = 8.0Hz) , 7.05 (d, 1H, J = 1.6Hz), 6.95 (s, 1H), 6.72 (s, 1H), 6.52 (s, 1H), 4.16-4.13 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.67 (s, 3H), 1.12 (d, 3H, J = 6.4 Hz), 0.64 (d, 3H, J = 6.4 Hz).

Example 59

6-chloro-5'-(3-chloro-4-fluorophenyl)-3'-isopropyl-2'-(4-methoxypyridin-3-yl)-3'H-spiro[dihydroindole- 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chloro-4-fluorophenyl)-3'-iso Propyl-2'-(4-methoxypyridin-3-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'( 17.9 mg of 5'H)-dione (S-59); (R)-6-chloro-5'-(3-chloro-4-fluorophenyl)-3'-isopropyl-2'-(4-methoxypyridin-3-yl)-3'H-spiro[ 22.5 mg of dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-59) was obtained. MS (ESI): mass calcd. for: C ₂₇ H ₂₀ Cl ₂ FN ₅ O ₃ , 551.1 m/z found 552.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 8.64 (d, 1H, J =6.4Hz), 8.48 (brs, 1H), 7.54 (d, 1H, J =8.0Hz), 7.44-7.42 (m, 1H), 7.40-7.14 (m, 4H), 7.08-6.97 (m, 2H), 4.09-4.03 (m, 1H), 3.88 (s, 3H), 1.11 (d, 3H, J =6.4Hz), 0.64 (d, 3H, J =6.4 Hz).

Example 60

2-Chloro-4-(6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-2,6'-dioxo-3',6'- Dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-5'-yl)benzamide

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-2-chloro-4-(6-chloro-2'-(2,4-dimethoxypyrimi). Din-5-yl)-3'-isopropyl-2,6'-dioxo-3',6'-dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3, 14.0 mg of 4-d]imidazole]-5'-yl)benzamide (S-60); (R)-2-chloro-4-(6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-2,6'-dioxo-3',6'-dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-5'-yl)benzamide (R-60) 16.3mg Obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₃ Cl ₂ N ₇ O ₅ 607.1, m/z found 608.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO- d ₆ ) δ 11.69 (brs, 1H), 8.51 (s, 1H), 7.91 (s, 1H), 7.59 (s, 1H), 7.50 (d, 1H, J = 7.2 Hz), 7.40 (d, 1H, J = 8.0Hz), 7.16-7.14 (m, 2H), 7.06-6.99 (m, 2H), 4.17-4.14 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.13 (d, 3H, J = 6.4 Hz), 0.63 (d, 3H, J = 6.4 Hz).

Example 61

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (S-61) 29.9mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro 26.3 mg of [dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-61) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₅ C _l2 N ₅ O ₄ 577.1, m/z found 578.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.49 (s, 1H), 8.50 (d, 1H, J = 8.4Hz), 7.62 (d, 1H, J = 8.4Hz), 7.54 (d, 1H, J = 9.2Hz), 7.36-7.33 (m, 1H), 7.27 (d, 1H, J = 8.0Hz),7.04-7.00 (m, 1H), 6.73-6.79 (m, 2H), 4.10 (t, 1H) , J = 6.8Hz), 3.84 (s, 3H), 3.79 (s, 3H), 2.42-2.27 (m, 3H), 1.07 (d, 3H, J = 4.8Hz), 0.638 (d, 3H, J = 4.8Hz).

Example 62

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-methoxy-5-methylphenyl)-3'H-spiro[dihydroindole-3,4 '-Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(2-methoxy-5-methylphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H )-Dione (S-62) 40.0mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-methoxy-5-methylphenyl)-3'H-spiro[dihydroindole 44.0 mg of -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-62) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₄ O ₃ , 560.1 m/z found 561.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.72 (brs, 1H), 7.55-6.97 (m, 10H), 4.09-4.05 (m, 1H), 3.75 (s, 3H), 2.30 (s, 3H) ), 2.22 (s, 3H), 1.07 (d, 3H, J =5.6Hz), 0.63 (d, 3H, J =5.6Hz).

Example 63

6-chloro-5'-(3-chloro-4-methoxyphenyl)-3'-isopropyl-2'-(2-methoxyphenyl)-3'H-spiro[dihydroindole-3,4' -Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chloro-4-methoxyphenyl)-3'-iso Propyl-2'-(2-methoxyphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H) -22.9 mg of dione (S-63); (R)-6-chloro-5'-(3-chloro-4-methoxyphenyl)-3'-isopropyl-2'-(2-methoxyphenyl)-3'H-spiro[dihydroindole- 22.9 mg of 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-63) were obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₄ Cl ₂ N ₄ O ₄ , 563.4 m/z found 564.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 7.57-6.91 (m, 10H),4.08-4.00 (m, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 1.08 (m, 3H ), 0.75-0.70 (m, 3H).

Example 64

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxyphenyl)-3'H-spiro[dihydroindole-3,4'-pi Lolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(4-methoxyphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (S-64) 73.9 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxyphenyl)-3'H-spiro[dihydroindole-3, 79.7 mg of 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-64) were obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₄ Cl ₂ N ₄ O ₃ 546.1, m/z found 547.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.73 (brs, 1H), 7.58-6.45 (m, 10H), 4.46-4.43 (m, 1H), 3.83 (s, 3H), 2.21 (s, 3H) ), 1.11-1.09 (d, 3H, J =6.4Hz), 0.75 (d, 3H, J =6.4Hz).

Example 65

2-Chloro-4-(6-chloro-2'-(4,6-dimethoxypyridin-3-yl)-3'-isopropyl-2,6'-dioxo-3',6'-dihydro -5'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-5'-yl)benzamide

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-2-chloro-4-(6-chloro-2'-(4,6-dimethoxypyridine-). 3-yl)-3'-isopropyl-2,6'-dioxo-3',6'-dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3,4- d]imidazole]-5'-yl)benzamide (S-65) 7.3 mg; (R)-2-chloro-4-(6-chloro-2'-(4,6-dimethoxypyridin-3-yl)-3'-isopropyl-2,6'-dioxo-3',6 10.3 mg of'-dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-5'-yl)benzamide (R-65) was obtained. . MS (ESI): mass calcd. for C ₂₉ H ₂₄ Cl ₂ N ₆ O ₅ 606.1, m/z found 607.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.63 (brs, 1H), 8.11(s, 1H), 7.91 (s, 1H), 7.59 (s, 1H), 7.51 (d, 1H, J = 8.0 Hz), 7.41 (d, 1H, J = 8.4Hz), 7.16-7.14 (m, 2H), 7.04-7.01 (m, 1H), 7.01-6.99 (m, 1H), 6.59 (s, 1H), 4.07 -4.03 (m, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 1.11 (d, 3H, J = 6.0 Hz), 0.61 (d, 3H, J = 6.0 Hz).

Example 66

2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-(5-chloro-2-fluorophenyl)-3'-isopropyl-3'H-spiro[dihydroindole- 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-( 5-Chloro-2-fluorophenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'( 12.7 mg of 5'H)-dione (S-66); (R)-2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-(5-chloro-2-fluorophenyl)-3'-isopropyl-3'H-spiro[ 10.1 mg of dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-66) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₂ Cl ₂ FN ₅ O ₃ 565.1, m/z found 566.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 7.70-7.00 (m, 7H), 6.31 (s, 1H), 6.23 (d, 1H, J =9.2Hz), 5.59 (brs, 2H), 4.12- 4.07 (m, 1H), 3.67 (s, 3H), 1.07 (d, 3H, J =5.6Hz), 0.60 (d, 3H, J =5.6Hz).

Example 67

2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-(3-chloro-5-fluorophenyl)-3'-isopropyl-3'H-spiro[dihydroindole- 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-( 3-Chloro-5-fluorophenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'( 21.3 mg of 5'H)-dione (S-67); (R)-2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-(3-chloro-5-fluorophenyl)-3'-isopropyl-3'H-spiro[ 18.8 mg of dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-67) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₂ Cl ₂ FN ₅ O ₃ 565.1, m/z found 566.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 7.35-7.28 (m, 2H), 7.02-6.92 (m, 5H), 6.29 (s, 1H), 6.24 (d, 1H, J =8.0Hz), 5.57 (brs, 2H), 4.10-4.04 (m, 1H), 3.65 (s, 3H), 1.09 (d, 3H, J =6.4Hz), 0.57 (d, 3H, J =6.4Hz).

Example 68

4-(6-Chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-3-methoxy-N,N-dimethylbenzamide

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-4-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'- Isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2' -Yl)-3-methoxy-N,N-dimethylbenzamide (S-68) 13.4 mg; (R)-4-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H -Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-3-methoxy-N,N-dimethylbenzamide (R-68) 17.1mg Was obtained. MS (ESI): mass calcd. for C ₃₂ H ₂₉ Cl ₂ N ₅ O ₄ , 617.2 m/z found 618.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.73 (brs, 1H), 7.58-6.97 (m, 9H), 4.10-4.07 (m, 1H), 3.82 (s, 3H), 3.01 (s, 3H) ), 2.96 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J =6.4Hz), 0.65 (d, 3H, J =6.4Hz).

Example 69

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-isopropoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6- Isopropoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-69) 9.6mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-isopropoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3' 28.9 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-69) was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₉ Cl ₂ N ₅ O ₄ , 605.2 m/z found 606.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.54 (brs, 1H), 8.10 (d, J = 4.4 Hz, 1H), 7.56-6.96 (m, 7H), 5.36-5.30 (m, 1H), 4.08-4.05 (m, 1H), 3.83 (s, 3H), 2.21 (s, 3H), 1.33 (d, J = 6.4 Hz, 6H), 1.08 (d, J = 5.2 Hz, 3H), 0.64 (d , J = 5.2 Hz, 3H).

Example 70

2-(3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H- Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxyphenyl)-N,N-dimethylacetamide

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-2-(3-(6-chloro-5'-(5-chloro-2-methylphenyl)- 3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole] -2'-yl)-4-methoxyphenyl)-N,N-dimethylacetamide (S-70) 25.9 mg; (R)-2-(3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro- 3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxyphenyl)-N,N-dimethylacetamide (R -70) 30.7 mg was obtained. MS (ESI): mass calcd. for C ₃₃ H ₃₁ Cl ₂ N ₅ O ₄ 631.2, m/z found 632.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.72 (brs, 1H), 7.57-6.96 (m, 9H), 4.09-4.06 (m, 1H), 3.78 (s, 3H), 3.69 (s, 2H) ), 3.01 (s, 3H), 2.83 (s, 3H), 2.22 (s, 3H), 1.07 (s, 3H), 0.36 (s, 3H).

Example 71

2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-(3-chloro-4-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole- 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-( 3-Chloro-4-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'( 17.1 mg of 5'H)-dione (S-71); (R)-2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-(3-chloro-4-methoxyphenyl)-3'-isopropyl-3'H-spiro[ 16.1 mg of dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-71) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₅ Cl ₂ N ₅ O ₄ , 577.1 m/z found 578.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 7.20-6.20 (m, 9H), 5.49 (s, 2H), 3.98 (m, 1H), 3.78 (s, 3H), 3.64 (s, 3H), 1.11-1.05 (m, 3H), 0.60-0.59 (m, 3H).

Example 72

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-ethoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6- Ethoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2, 20.2 mg of 6'(5'H)-dione (S-72); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-ethoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H 23.2 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-72) were obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₇ Cl ₂ N ₅ O ₄ 591.1, m/z found 592.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.73 (brs, 1H), 8.10 (s, 1H), 7.56-7.44 (m, 1H), 7.31-6.48 (m,6H),4.40 (brs, 2H) ), 4.06-4.02 (m,1H), 3.84 (s, 3H), 2.21 (s, 3H), 1.36 (t, 3H, J =7.6Hz), 1.08 (d, 3H, J =6.4Hz), 0.64 (d, 3H, J =6.4 Hz).

Example 73

2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-(3-chloro-4-fluorophenyl)-3'-isopropyl-3'H-spiro[dihydroindole- 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-( 3-Chloro-4-fluorophenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'( 24.7 mg of 5'H)-dione (S-73); (R)-2'-(4-amino-2-methoxyphenyl)-6-chloro-5'-(3-chloro-4-fluorophenyl)-3'-isopropyl-3'H-spiro[ 28.7 mg of dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-73) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₂ Cl ₂ FN ₅ O ₃ 565.1, m/z found 566.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 7.39-7.34 (m, 1H), 7.27-7.21 (m, 2H), 7.03-6.90 (m, 4H), 6.29 (s, 1H), 6.24 (d , 1H, J = 8.0Hz), 5.56 (brs, 2H), 4.08-4.05 (m, 1H), 3.65 (s, 3H), 1.08 (s, 3H), 0.59 (s, 3H).

Example 74

2'-(4-amino-2-methoxy-5-methylphenyl)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H-spiro[dihydroindole -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-2'-(4-amino-2-methoxy-5-methylphenyl)-6-chloro-5. '-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (S-74) 25.0 mg; (R)-2'-(4-amino-2-methoxy-5-methylphenyl)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H-spiro 26.6 mg of [dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-74) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₇ Cl ₂ N ₅ O ₃ 575.1, m/z found 576.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.68 (brs, 1H), 7.51-6.93 (m, 8H), 5.33 (brs, 2H), 4.12-4.10 (m, 1H), 3.66 (s, 3H) ), 2.21 (s, 3H), 2.01 (s, 3H), 1.05 (d, 3H, J =6.4Hz), 0.61 (d, 3H, J =6.4Hz).

Example 75

2'-(4-amino-5-fluoro-2-methoxyphenyl)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

Following similar steps as in Example 1 to obtain the title compound, and subjected to supercritical high pressure preparative chromatography (S)-2'-(4-amino-5-fluoro-2-methoxyphenyl)-6-chloro -5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2, 7.8 mg of 6'(5'H)-dione (S-75); (R)-2'-(4-amino-5-fluoro-2-methoxyphenyl)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H 12.7 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-75) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₄ Cl ₂ FN ₅ O ₃ 579.1, m/z found 580.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.54 (brs, 1H), 7.49-6.46 (m, 8H), 5.65 (brs, 2H), 4.13-4.11 (m, 1H), 3.67 (s, 3H) ), 2.21 (s, 3H), 1.06 (s, 3H, J =6.0Hz), 0.62 (d, 3H, J =6.0Hz).

Example 76

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(3-fluoro-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3 ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(3- Fluoro-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5 'H)-dione (S-76) 22.0 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(3-fluoro-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[di 25.1 mg of hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-76) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₃ Cl ₂ FN ₄ O ₃ 564.1, m/z found 565.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.51 (brs, 1H), 7.57-6.95 (m, 9H), 4.11-4.10 (m, 1H), 3.77 (s, 3H), 2.22 (s, 3H) ), 1.08 (d, 3H, J =6.0Hz), 0.66 (d, 3H, J =6.0Hz).

Example 77

4-(6-Chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-3-methoxybenzamide

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-4-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'- Isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2' -Yl)-3-methoxybenzamide (S-77) 23.6 mg; (R)-4-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H 21.5 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-3-methoxybenzamide (R-77) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₅ Cl ₂ N ₅ O ₄ , 589.1 m/z found 590.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.76 (brs, 1H), 8.14 (brs, 2H), 7.64-6.98 (m, 9H), 4.08-4.06 (m, 1H), 3.85 (s, 3H) ), 2.22 (s, 3H), 1.07 (d, 3H, J =4.8Hz), 0.64 (d, 3H, J =4.8Hz).

Example 78

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-dimethylamino)-5-fluoro-2-methoxyphenyl)-3'-isopropyl-3'H-spiro [Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4- Dimethylamino)-5-fluoro-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]- 19.7 mg of 2,6'(5'H)-dione (S-78); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-dimethylamino)-5-fluoro-2-methoxyphenyl)-3'-isopropyl-3 28.3 mg of'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-78) was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₈ Cl ₂ FN ₅ O ₃ 607.2, m/z found 608.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.54 (brs, 1H), 7.52-6.57 (m, 9H), 4.12-4.10 (m, 1H), 3.78 (s, 3H), 2.91 (s, 6H) ), 2.21 (s, 3H), 1.06 (d, 3H, J =4.0Hz), 0.63 (d, 3H, J =4.0Hz).

Example 79

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,6-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4' -Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2, 6-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H) -23.7 mg of dione (S-79); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,6-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole- 24.7 mg of 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-79) were obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₄ O ₄ 576.1, m/z found 577.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.70 (brs, 1H), 7.51-6.78 (m, 9H), 3.90-3.83 (m, 1H), 3.75 (s, 3H), 3.71 (s, 3H) ), 2.24 (s, 3H), 1.02 (d, 3H, J=6.8Hz), 0.61 (d, 3H, J=6.8Hz ) .

Example 80

6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3, 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-( 2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5' H)-dione (S-80) 32.0mg; (R)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydro 35.4 mg of indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-80) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₃ Cl ₂ FN ₄ O ₄ 580.1, m/z found 581.2 [M+H] ⁺ . 1H-NMR (400MHz, DMSO-d ₆ ) δ 11.85 (brs, 1H), 7.48-6.66 (m, 9H), 4.09-4.03 (m, 1H), 3.84 (s,3H), 3.77 (s, 3H) , 1.04 (d, 3H, J=6.0Hz), 0.61 (d, 3H, J=6.0Hz).

Example 81

6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(4-(dimethylamino)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-( 4-(dimethylamino)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2, 26.0 mg of 6'(5'H)-dione (S-81); (R)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(4-(dimethylamino)-2-methoxyphenyl)-3'-isopropyl-3'H 19.5 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-81) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ FN ₅ O ₃ 593.13, m/z found 594.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.52 (brs, 1H), 7.46-7.05 (m, 6H), 6.98 (s, 1H), 6.40 (d, 1H, J =8.4Hz), 6.35 ( s, 1H), 4.12-4.08 (m, 1H), 3.76 (s,3H), 2.99 (s, 6H), 1.08 (d, 3H, J =5.6Hz), 0.61 (d, 3H, J =5.6Hz ).

Example 82

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H- Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2- (Dimethylamino)-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole] -2,6'(5'H)-dione (S-82) 13.7mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3'-isopropyl- 13.6 mg of 3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-82) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₇ Cl ₂ N ₇ O ₃ 591.15, m/z found 592.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 8.25 (d, 1H, J =4.4Hz), 7.55-6.97 (m, 6H), 4.15-4.12 (m, 1H), 3.90 (s, 3H), 3.19 (s, 6H), 2.20 (s, 3H), 1.08 (d, 3H, J =6.4Hz), 0.66 (d, 3H, J =6.4Hz).

Example 83

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxy-5-methylphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3 ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2, 4-dimethoxy-5-methylphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5 'H)-dione (S-83) 48.6 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxy-5-methylphenyl)-3'-isopropyl-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-83) 30.5mg was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₈ Cl ₂ N ₄ O ₄ 590.19, m/z found 591.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.52 (brs, 1H), 7.47-7.04 (m, 6H), 6.98 (d, 1H, J =1.6Hz), 6.40 (d, 1H, J =8.4 Hz), 6.35 (s, 1H), 4.12-4.08 (m, 1H), 3.76 (s, 3H), 2.99 (s, 6H), 2.22 (s, 3H), 1.08 (d, 3H, J =6.4Hz ), 0.61 (d, 3H, J =6.4 Hz).

Example 84

3-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxybenzoic acid

Following similar steps as in Example 1, 80 mg of the title compound was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₄ Cl ₂ N ₄ O ₅ , 590.11 m/z found 591.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.35 (brs, 1H), 8.12 (d, 1H, J = 8.0 Hz), 7.96 (s, 1H), 7.60-6.97 (m, 7H), 4.07- 4.06 (m, 1H), 3.87 (s, 3H), 2.23 (s, 3H), 1.17 (d, 3H, J =7.2 Hz), 0.62 (d, 3H, J =7.2 Hz).

Example 85

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-methoxy-4-(trifluoromethyl)phenyl)-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(2-methoxy-4-(trifluoromethyl)phenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2, 10.1 mg of 6'(5'H)-dione (S-85); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-methoxy-4-(trifluoromethyl)phenyl)-3'H 9.7 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-85) were obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₃ Cl ₂ F ₃ N ₄ O ₃ 614.11, m/z found 615.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 7.71-6.98 (m, 9H), 4.08-4.06 (m, 1H), 3.89 (s, 3H), 2.22 (s, 3H) ,1.18 (d, 3H) , J =4.0Hz), 0.64 (d, 3H, J =4.0Hz).

Example 86

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-cyclopropyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3 ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4- Cyclopropyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5 18.7 mg of'H)-dione (S-86); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-cyclopropyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[di 21.2 mg of hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-86) was obtained. MS (ESI): mass calcd. for C ₃₂ H ₂₈ Cl ₂ N ₄ O ₃ 586.15 m/z found 587.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.57 (brs, 1H), 7.53-6.47 (m, 9H), 4.07-4.03 (m, 1H), 3.78 (s, 3H), 2.21 (s, 3H) ), 2.01-2.00 (m, 1H), 1.16 (d, 3H, J =6.4Hz), 1.05-1.00 (m, 4H), 0.64 (d, 3H, J =6.4Hz).

Example 87

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-methoxy-4-(trifluoromethoxy)phenyl)-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(2-methoxy-4-(trifluoromethoxy)phenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2, 45.1 mg of 6'(5'H)-dione (S-87); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-methoxy-4-(trifluoromethoxy)phenyl)-3'H -Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-87) 44.6 mg was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₃ Cl ₂ F ₃ N ₄ O ₄ , 630.10 m/z found 631.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.74 (brs, 1H), 7.60-6.48 (m, 9H), 4.07-4.02 (m, 1H), 3.84 (s, 3H), 2.22 (s, 3H) ), 1.14 (d, 3H, J = 4.8 Hz), 0.64 (d, 3H, J = 4.8 Hz).

Example 88

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-ethoxy-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3 ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4- Ethoxy-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5 36.2 mg of'H)-dione (S-88); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-ethoxy-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-88) 42.5mg was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₈ C _l2 N ₄ O ₄ 590.15 m/z found 591.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.54 (brs, 1H), 7.54-6.95 (m, 9H), 4.14-4.04 (m, 3H), 3.77 (s, 3H), 2.22 (s, 3H) ), 1.36 (t, 3H, J = 6.8 Hz), 1.05 (d, 3H, J = 5.2 Hz), 0.62 (d, 3H, J = 5.2 Hz).

Example 89

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-3'-isopropyl-2'-(4-isopropyl-2-methoxyphenyl)-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-3. '-Isopropyl-2'-(4-isopropyl-2-methoxyphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-89) 43.2mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-3'-isopropyl-2'-(4-isopropyl-2-methoxyphenyl)-3' 32.4 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-89) was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₉ Cl ₂ N ₅ O ₃ 589.16, m/z found 590.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.69 (brs, 1H), 8.50 (d, 1H, J =8.0Hz), 7.64-7.00 (m, 7H), 4.09-4.06 (m, 1H), 3.79 (s, 3H), 3.01-2.94 (m, 1H), 2.42 (s, 3H), 1.35 (d, 3H, J =7.6Hz), 1.27 (d, 3H, J =7.6Hz), 1.07 (d , 3H, J =4.0Hz), 0.64 (d, 3H, J =4.0Hz).

Example 90

2'-(2-amino-4-methoxypyrimidin-5-yl)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

Following similar steps as in Example 1 to obtain the title compound, and subjected to supercritical high pressure preparative chromatography (S)-2'-(2-amino-4-methoxypyrimidin-5-yl)-6-chloro -5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2, 19.0 mg of 6'(5'H)-dione (S-90); (R)-2'-(2-amino-4-methoxypyrimidin-5-yl)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H 17.4 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-90) was obtained. MS (ESI): mass calcd. for C ₂₇ H ₂₃ Cl ₂ N ₇ O ₃ 563.12, m/z found 564.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.57 (brs, 1H), 8.14 (d, 1H, J =4.8Hz), 7.54-6.96 (m, 8H), 4.18-4.13 (m, 1H), 3.84 (s, 3H), 2.20 (s, 3H), 1.08 (d, 3H, J =4.4Hz), 0.67 (d, 3H, J =4.4Hz).

Example 91

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-(dimethylamino)-2-methoxy-5-methylphenyl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4- (Dimethylamino)-2-methoxy-5-methylphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 , 6'(5'H)-dione (S-91) 29.2mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-(dimethylamino)-2-methoxy-5-methylphenyl)-3'-isopropyl-3' 17.8 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-91) was obtained. MS (ESI): mass calcd. for C ₃₂ H ₃₁ Cl ₂ N ₅ O ₃ 603.18, m/z found 604.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.51 (brs, 1H), 7.53-6.47 (m, 8H), 4.11-4.08 (m, 1H), 3.77 (s, 3H), 2.73 (s, 6H) ), 2.22 (s, 3H), 2.07 (s, 3H), 1.06 (d, 3H, J =4.4Hz), 0.62 (d, 3H, J =4.4Hz).

Example 92

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(5-fluoro-2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(5- Fluoro-2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6' 29.1 mg of (5'H)-dione (S-92); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(5-fluoro-2,4-dimethoxyphenyl)-3'-isopropyl-3'H-spiro 33.8 mg of [dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-92) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₅ Cl ₂ FN ₄ O ₄ 594.13, m/z found 595.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d6) δ 11.75 (brs, 1H), 7.53-6.47 (m, 8H), 4.10-4.07 (m, 1H), 3.96 (s, 3H), 3.82 (s, 3H) , 2.21 (s, 3H), 1.07 (d, 3H, J =4.4Hz), 0.63 (d, 3H, J =4.4Hz).

Example 93

6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'-(4-isopropyl-2-methoxyphenyl)-3'H-spiro[dihydroindole-3,4' -Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to (S)-6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'- (4-isopropyl-2-methoxyphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H) -125.0 mg of dione (S-93); (R)-6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'-(4-isopropyl-2-methoxyphenyl)-3'H-spiro[dihydroindole- 132.7 mg of 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-93) was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₈ C _l2 N ₄ O ₃ 574.15, m/z found 575.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.58 (brs, 1H), 7.49 (d, 1H, J =8.0Hz), 7.38-6.95 (m, 9H), 4.09-4.02 (m, 1H), 3.78 (s, 3H), 3.01-2.94 (m, 1H), 1.27 (d, 6H, J =7.2Hz), 1.09 (d, 3H, J =6.4Hz), 0.59 (d, 3H, J =6.4Hz ).

Example 94

6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(4-ethoxy-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-( 4-Ethoxy-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (S-94) 7.8 mg; (R)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(4-ethoxy-2-methoxyphenyl)-3'-isopropyl-3'H-spiro 15.2 mg of [dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-94) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₅ Cl ₂ FN ₄ O ₄ 594.12, m/z found 595.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.01 (brs, 1H), 7.48-6.64 (m, 9H), 4.14-4.04 (m, 3H), 3.76 (s, 3H), 1.37-1.18 (m , 3H), 1.04 (d, 3H, J =6.4Hz), 0.62 (d, 3H, J =6.4Hz).

Example 95

6-chloro-5'-(3-chlorophenyl)-2'-(6-isopropoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(6-isopropoxy -4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6' 100.8 mg of (5'H)-dione (S-95); (R)-6-chloro-5'-(3-chlorophenyl)-2'-(6-isopropoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro 108.8 mg of [dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-95) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₇ Cl ₂ N ₅ O ₄ 591.14, m/z found 592.1[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.53 (brs, 1H), 8.08 (s, 1H), 7.48 (d, 1H, J =8.4Hz), 7.38 (d, 1H, J =8.0Hz) , 7.34 (d, 1H, J =8.4Hz), 7.14 (d, 2H, J =9.2Hz), 7.00 (d, 1H, J =1.6Hz), 6.97 (d, 1H, J =7.2Hz), 6.51 (s, 1H), 5.36-5.29 (m, 1H), 4.11-4.04 (m, 1H), 3.82 (s, 1H), 1.33 (d, 6H, J =6.0Hz), 1.11 (d, 3H, J =6.4Hz), 0.61 (d, 3H, J =6.4Hz).

Example 96

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(6-ethoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3' H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(6-ethoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d] already Dazole]-2,6'(5'H)-dione (S-96) 27.1 mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(6-ethoxy-4-methoxypyridin-3-yl)-3'-iso 29.6 mg of propyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-96) was obtained. I did. MS (ESI): mass calcd. for C ₂₉ H ₂₆ Cl ₂ N ₆ O ₄ 592, m/z found 593.1[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.80 (brs, 1H), 8.50 (d, 1H, J =8.0Hz), 8.12 (d, 1H, J =4.8Hz), 7.64-7.00 (m, 4H), 6.58 (s, 1H), 4.40 (q, 2H, J =7.2Hz), 4.09-4.04 (m, 1H), 3.84 (s, 3H), 2.27 (s, 3H), 1.36 (t, 3H , J =7.2Hz), 1.08 (d, 3H, J =6.8Hz), 0.65 (d, 3H, J =4.0Hz).

Example 97

6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(2-ethoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H- Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-( 2-Ethoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole] 0.8mg -2,6'(5'H)-dione (S-97); (R)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(2-ethoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl- 3.3 mg of 3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-97) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₃ Cl ₂ FN ₆ O ₄ 596.11, m/z found 597.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.59 (brs, 1H), 8.51 (s, 1H), 7.48-7.00 (m, 6H), 4.46 (q, 2H, J =6.8Hz), 4.10- 4.07 (m, 1H), 3.94 (s, 3H), 1.39 (t, 3H, J =6.8Hz), 1.11 (d, 3H, J =6.4Hz), 0.66 (d, 3H, J =6.4Hz).

Example 98

6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(6-ethoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro [Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-( 6-Ethoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]- 17.5 mg 2,6'(5'H)-dione (S-98); (R)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(6-ethoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3 20.7 mg of'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-98) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₄ Cl ₂ FN ₅ O ₄ 595.11, m/z found 596.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.60 (brs, 1H), 8.11 (s, 1H), 7.48-7.00 (m, 6H), 6.57 (s, 1H), 4.40 (q, 2H, J =6.8Hz), 4.08-4.04 (m, 1H), 3.83 (s, 3H), 1.35 (t, 3H, J =6.8Hz), 1.08 (d, 3H, J =6.4Hz), 0.64 (d, 3H, J =6.4 Hz).

Example 99

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-(ethyl(methyl)amino)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4- (Ethyl(methyl)amino)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-99) 42.0mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-(ethyl(methyl)amino)-2-methoxyphenyl)-3'-isopropyl-3' 41.2 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-99) was obtained. MS (ESI): mass calcd. for C ₃₂ H ₃₁ Cl ₂ N ₅ O ₃ 603, m/z found 604.2[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.69 (brs, 1H), 7.54-6.96 (m, 7H), 6.46-6.32 (m, 2H), 4.11-4.10 (m, 1H), 3.76 (s , 3H), 3.47-3.45 (m, 2H), 2.95 (s, 3H), 2.21 (s, 3H), 1.11-1.07 (m, 6H), 0.62 (d, 3H, J =6.4 Hz).

Example 100

6-chloro-5'-(3-chlorophenyl)-2'-(4-ethoxy-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4' -Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(4-ethoxy- 2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H) -19.1 mg of dione (S-100); (R)-6-chloro-5'-(3-chlorophenyl)-2'-(4-ethoxy-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole- 21.3 mg of 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-100) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₄ O ₄ 576.13, m/z found 577.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.56 (brs, 1H), 7.45 (d, 1H, J =8.0Hz), 7.37-6.94 (m, 7H), 6.69 (s, 1H), 6.66 ( d, 1H, J =8.4Hz), 7.00-6.94 (m, 2H), 4.14-4.03 (m, 3H), 3.76 (s, 3H), 1.37 (t, 3H, J =6.8Hz), 1.04 (d , 3H, J =6.4Hz), 0.60 (d, 3H, J =6.4Hz).

Example 101

2'-(4-(tert-butyl)-2-methoxyphenyl)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H-spiro[dihydro Indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to (S)-2'-(4-(tert-butyl)-2-methoxyphenyl)-6-chloro- 5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6 17.1 mg of'(5'H)-dione (S-101); (R)-2'-(4-(tert-butyl)-2-methoxyphenyl)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H- 17.2 mg of spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-101) was obtained. MS (ESI): mass calcd. for C ₃₃ H ₃₂ Cl ₂ N ₄ O ₃ 602.2, m/z found 603.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 7.56-6.48 (m, 9H), 4.08-4.07 (m, 1H), 3.81 (s, 3H), 2.22 (s, 3H), 1.35 (s, 9H) ), 1.07 (d, 3H, J = 5.2Hz), 0.62 (d, 3H, J =5.2Hz).

Example 102

6-Chloro-5'-(3-chlorophenyl)-2'-(6-ethoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole- 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(6-ethoxy- 4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'( 53.4 mg of 5'H)-dione (S-102); (R)-6-chloro-5'-(3-chlorophenyl)-2'-(6-ethoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[ 55.0 mg of dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-102) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₅ Cl ₂ N ₅ O ₄ 577.13, m/z found 578.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.54 (brs, 1H), 8.09 (s, 1H), 7.48 (d, 1H, J =8.0Hz), 7.38 (d, 1H, J =8.4Hz) , 7.34 (s, 1H), 7.14-7.12 (m, 2H), 7.00 (s, 1H), 6.97 (d, 1H, J =7.2Hz), 6.57 (s, 1H), 4.40 (q, 2H, J =6.8Hz), 4.07-4.02 (m, 1H), 3.83 (s, 3H), 1.35 (t, 3H, J =6.8Hz), 1.10 (d, 3H, J =6.4Hz), 0.62 (d, 3H) , J =6.4Hz).

Example 103

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-cyclopropyl-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6- Cyclopropyl-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2, 39.5 mg of 6'(5'H)-dione (S-103); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-cyclopropyl-4-methoxypyridin-3-yl)-3'-isopropyl-3'H -Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-103) 32.7mg was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₇ Cl ₂ N ₅ O ₃ 587, m/z found 588.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.72 (brs, 1H), 8.30 (d, 1H, J =4.0Hz), 7.57-6.97 (m, 7H), 4.08-4.06 (m, 2H), 3.88 (s, 3H), 2.21 (s, 3H), 2.07-1.98 (m, 4H), 1.08 (d, 3H, J =6.0Hz), 0.66 (d, 3H, J =6.0Hz).

Example 104

6-chloro-5'-(3-chlorophenyl)-2'-(4-(dimethylamino)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3, 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(4-(dimethylamino). )-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5' 80.2 mg of H)-dione (S-104); (R)-6-chloro-5'-(3-chlorophenyl)-2'-(4-(dimethylamino)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydro 70.0 mg of indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-104) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₇ C _l2 N ₅ O ₃ 575.15, m/z found 576.6[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.50 (brs, 1H), 7.45 (d, 1H, J =8.0Hz), 7.37-7.30 (m, 2H), 7.17-7.11 (m, 3H), 7.00-6.94 (m, 2H), 6.40-6.35 (m, 2H), 4.13-4.06 (m, 1H), 4.06 (s, 3H), 3.76 (s, 3H), 2.99 (s, 6H), 1.09 ( d, 3H, J =6.0Hz), 0.60 (d, 3H, J =6.0Hz).

Example 105

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-(diethylamino)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydro Indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4- (Diethylamino)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6 11.6 mg of'(5'H)-dione (S-105); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-(diethylamino)-2-methoxyphenyl)-3'-isopropyl-3'H- 16.3 mg of spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-105) was obtained. MS (ESI): mass calcd. for C ₃₃ H ₃₃ Cl ₂ N ₅ O ₃ 617.19, m/z found 618.5 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.68 (brs, 1H), 7.54-6.94 (m, 7H), 6.46-6.27 (m, 2H), 4.14-4.11 (m, 1H), 3.75 (s , 3H), 3.42-3.40 (m, 4H), 2.21 (s, 3H), 1.16-1.12 (m, 6H), 1.06 (d, 3H, J =5.2Hz), 0.62 (d, 3H, J =5.2 Hz).

Example 106

6-chloro-5'-(3-chlorophenyl)-2'-(6-cyclopropyl-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole- 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(6-cyclopropyl- 4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'( 47.4 mg of 5'H)-dione (S-106); (R)-6-chloro-5'-(3-chlorophenyl)-2'-(6-cyclopropyl-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[ 57.5 mg of dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-106) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₅ Cl ₂ N ₅ O ₃ 573, m/z found 574.3[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.56 (brs, 1H), 8.33 (s, 1H), 7.49 (d, 1H, J =8.0Hz), 7.36-6.95 (m, 8H), 4.08- 4.06 (m, 1H), 3.89(s, 3H), 2.15-2.00 (m, 1H), 1.05 (d, 3H, J =6.0Hz), 1.03-0.98 (m, 4H), 0.62 (d, 3H, J =6.0Hz).

Example 107

6-chloro-5'-(3-chlorophenyl)-2'-(4-ethyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'- Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(4-ethyl-2. -Methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)- 49.1 mg of dione (S-107); (R)-6-chloro-5'-(3-chlorophenyl)-2'-(4-ethyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3 39.8 mg of ,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-107) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₄ O ₃ 560.13, m/z found 561.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.48 (brs, 1H), 7.48 (d, 1H, J =8.0Hz), 7.37-6.94 (m, 9H), 4.09-4.02 (m, 1H), 3.77 (s, 3H), 2.72 (q, 2H, J =7.6Hz), 1.26 (t, 3H, J =7.6Hz), 1.04 (d, 3H, J =6.0Hz), 0.61 (d, 3H, J =6.0Hz).

Example 108

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-cyclopropyl-2,6-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4- Cyclopropyl-2,6-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6' 28.4 mg (5'H)-dione (S-108); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-cyclopropyl-2,6-dimethoxyphenyl)-3'-isopropyl-3'H-spiro 29.9 mg of [dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-108) was obtained. MS (ESI): mass calcd. for C ₃₃ H ₃₀ Cl ₂ N ₄ O ₄ 616.16, m/z found 617.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.66 (brs, 1H), 7.45-6.48 (m, 8H), 3.89-3.88 (m, 1H), 3.73 (s, 3H), 3.70 (s, 3H) ), 2.23 (s, 3H), 2.07-2.00 (m, 1H), 1.01-0.99 (m, 5H), 0.84-0.83 (m, 2H), 0.60 (d, 3H, J =6.8 Hz).

Example 109

6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'-(2-methoxy-4-methylphenyl)-3'H-spiro[dihydroindole-3,4'-pi Lolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to (S)-6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'- (2-methoxy-4-methylphenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (S-108) 34.0 mg; (R)-6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'-(2-methoxy-4-methylphenyl)-3'H-spiro[dihydroindole-3, 43.5 mg of 4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-108) were obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₄ Cl ₂ N ₄ O ₃ 546.12, m/z found 547.4[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.53 (brs, 1H), 7.47-6.90 (m, 10H), 4.07-4.02 (m, 1H), 3.76 (s ,3H), 2.39 (s, 3H), 1.04 (d, 3H, J=6.0Hz), 0.59 (d, 3H, J=6.0Hz).

Example 110

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-cyclopropoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6- Cyclopropoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-109) 13.6mg; (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-cyclopropoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3' 13.1 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-109) was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₇ Cl ₂ N ₅ O ₄ 603.14, m/z found 604.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.73 (brs, 1H), 8.16-6.48 (m, 8H), 4.31-4.30 (m, 1H), 4.07-4.06 (m, 1H), 3.84 (s , 3H), 2.22 (s, 3H), 1.08 (d, 3H, J =5.6Hz), 0.82-0.80 (m, 2H), 0.79-0.71 (m, 2H), 0.65 (d, 3H, J =5.6 Hz).

Example 111

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro [Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6- (Dimethylamino)-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]- 44.9 mg of 2,6'(5'H)-dione (S-110); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3'-isopropyl-3 47.3 mg of'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-110) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₇ Cl ₂ N ₇ O ₃ 591, m/z found 592.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.52 (brs, 1H), 7.98-6.21 (m, 8H), 4.11-4.07 (m, 1H), 3.84 (s, 3H), 3.10 (s, 6H) ), 2.22 (s, 3H), 1.07 (d, 3H, J =6.0Hz), 0.63 (d, 3H, J =6.0Hz).

Example 112

6-chloro-5'-(3-chlorophenyl)-2'-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(2-(dimethylamino). )-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2, 50.9 mg of 6'(5'H)-dione (S-111); (R)-6-chloro-5'-(3-chlorophenyl)-2'-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H -Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-111) 46.6 mg was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₅ Cl ₂ N ₇ O ₃ 577.13, m/z found 578.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.52 (brs, 1H), 8.23 (s, 1H), 7.65-6.94 (m, 7H), 4.16-4.09 (m, 1H), 3.89 (s, 3H) ), 3.19 (s, 6H), 1.11 (d, 3H, J =6.8 Hz), 0.64 (d, 3H, J =6.4 Hz).

Example 113

6-chloro-5'-(3-chlorophenyl)-2'-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydro Indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(6-(dimethylamino). )-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6 45.0 mg of'(5'H)-dione (S-112); (R)-6-chloro-5'-(3-chlorophenyl)-2'-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3'-isopropyl-3'H- 34.4 mg of spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-112) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₆ Cl ₂ N ₆ O ₃ 576, m/z found 577.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.60 (brs, 1H), 8.06(s,1H), 7.44-6.96 (m, 7H), 6.39 (s, 1H), 4.12-4.05 (m, 1H) ), 3.92 (s, 3H), 3.20 (s, 6H), 1.12 (d, 3H, J =6.8 Hz), 0.63 (d, 3H, J =6.4 Hz).

Example 114

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxy-2-(pyrrolidin-1-yl)pyrimidin-5-yl) -3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(4-methoxy-2-(pyrrolidin-1-yl)pyrimidin-5-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4- d]imidazole]-2,6'(5'H)-dione (S-113) 10.1 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxy-2-(pyrrolidin-1-yl)pyrimidine- 5-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-113) 13.5 mg was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₉ Cl ₂ N ₇ O ₃ 617.17, m/z found 618.2[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.63 (brs, 1H), 8.24 (d, 1H, J =4.4Hz), 7.54-6.47 (m, 6H), 4.13-4.12 (m, 1H), 3.90 (s, 3H), 3.69-3.56 (m, 4H), 2.21 (s, 3H), 2.06-1.95 (m, 4H), 1.09 (d, 3H, J =5.2Hz), 0.66 (d, 3H, J =6.0Hz).

Example 115

6-chloro-5'-(3-chlorophenyl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4 '-Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(4,6-dime). Toxoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H )-Dione (S-114) 171.8mg; (R)-6-chloro-5'-(3-chlorophenyl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole 137.4 mg of -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-114) were obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₃ Cl ₂ N ₅ O ₄ 563.11, m/z found 564.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.57 (brs, 1H), 8.11 (s, 1H), 7.48-6.95 (m, 7H), 6.58 (s, 1H), 4.09-4.02 (m, 1H) ), 3.92 (s, 3H), 3.83 (s, 3H), 1.04 (d, 3H, J =3.6 Hz), 0.63 (d, 3H, J =6.4 Hz).

Example 116

6-chloro-5'-(3-chlorophenyl)-2'-(4-cyclopropyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4' -Pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(4-cyclopropyl- 2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H) -9.2 mg of dione (S-115); (R)-6-chloro-5'-(3-chlorophenyl)-2'-(4-cyclopropyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole- 9.2 mg of 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-115) was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₆ Cl ₂ N ₄ O ₃ 572.14, m/z found 573.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.06 (brs, 1H), 7.46-6.77 (m, 10H), 4.07-4.01 (m, 1H), 3.77 (s, 3H), 2.01-1.99 (m , 1H), 1.24-0.79 (m, 7H), 0.60 (d, 3H, J =4.4 Hz).

Example 117

2'-(2-(azetidin-1-yl)-4-methoxypyrimidin-5-yl)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-2'-(2-(azetidin-1-yl)-4-methoxypyrimidine-5 -Yl)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d ]Imidazole]-2,6'(5'H)-dione (S-116) 42.3mg; (R)-2'-(2-(azetidin-1-yl)-4-methoxypyrimidin-5-yl)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-Isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-116) 41.8mg Was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₇ Cl ₂ N ₇ O ₃ 603.15, m/z found 604.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.27 (brs, 1H), 8.22 (d, 1H, J =4.8Hz) 7.54-6.47 (m, 6H), 4.14 (t, 4H, J =7.2Hz ), 3.87 (s, 3H), 2.36-2.32 (m, 2H), 2.22 (s, 3H), 1.08 (d, 3H, J =5.2Hz), 0.66 (d, 3H, J =5.6Hz).

Example 118

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxy-2-methylpyrimidin-5-yl)-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(4-methoxy-2-methylpyrimidin-5-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2, 61.9 mg of 6'(5'H)-dione (S-117); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxy-2-methylpyrimidin-5-yl)-3'H 62.0 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-117) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₄ Cl ₂ N ₆ O ₃ 562, m/z found 563.4[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.73 (brs, 1H), 8.62 (d, 1H, J =6.4Hz), 7.57-6.48 (m, 6H), 4.15-4.12 (m, 1H), 3.96 (s, 3H), 2.63 (s, 3H), 2.22 (s, 3H), 1.09 (d, 3H, J =6.4Hz), 0.66 (d, 3H, J =6.4Hz).

Example 119

6-Chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-(ethyl(methyl)amino)-4-methoxypyrimidin-5-yl)-3'-isopropyl-3 'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2- (Ethyl(methyl)amino)-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d] Imidazole]-2,6'(5'H)-dione (S-118) 40.7 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-(ethyl(methyl)amino)-4-methoxypyrimidin-5-yl)-3'- 24.5 mg of isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-118) Obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₉ Cl ₂ N ₇ O ₃ 605.17, m/z found 606.4[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.61 (brs, 1H), 8.24 (d, 1H, J =4.0Hz), 7.55-6.47 (m, 6H), 4.16-4.15 (m, 1H), 3.89 (s, 3H), 3.69-3.68 (m, 2H), 3.15 (s ,3H), 2.21 (s, 3H), 1.23-1.16 (m, 3H), 1.09 (d, 3H, J =5.2Hz) , 0.66 (d, 3H, J =5.2 Hz).

Example 120

6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'-(2-methoxy-4-(trifluoromethoxy)phenyl)-3'H-spiro[dihydroindole- 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to (S)-6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'- (2-methoxy-4-(trifluoromethoxy)phenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'( 115.1 mg of 5'H)-dione (S-119); (R)-6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'-(2-methoxy-4-(trifluoromethoxy)phenyl)-3'H-spiro[ 44.0 mg of dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-119) was obtained. MS (ESI): mass calcd. for Chemical Formula: C ₂₉ H ₂₁ Cl ₂ F ₃ N ₄ O ₄ , Exact Mass: 616.09, m/z found 617.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.51 (brs, 1H), 7.57-7.47 (m, 2H), 7.38-7.34 (m, 2H), 7.21 (s, 1H), 7.14-7.09 (m , 3H), 7.00-6.96 (m, 2H), 4.06-4.03 (m, 1H), 3.88 (s, 3H), 1.10 (d, 3H, J =4.4Hz), 0.62 (d, 3H, J =4.4 Hz).

Example 121

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2- Cyclopropyl-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-120) 9.9mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3'-isopropyl-3' 9.4 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-120) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₆ O ₃ 588.14, m/z found 589.4[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.76 (brs, 1H), 8.54 (d, 1H, J =6.4Hz), 7.56-6.98 (m, 7H), 4.15-4.14 (m,1H), 3.94 (s, 3H), 2.21 (s, 3H), 2.07-1.99 (m, 1H), 1.35-1.08 (m, 7H), 0.66 (d, 3H, J =6.0Hz).

Example 122

6-chloro-5'-(3-chlorophenyl)-2'-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(2-cyclopropyl- 4-Methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6' 13.1 mg (5'H)-dione (S-121); (R)-6-chloro-5'-(3-chlorophenyl)-2'-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro 13.3mg of [dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-121) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₄ Cl ₂ N ₆ O ₃ 574.13, m/z found 575.4[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.55 (brs, 1H), 8.52 (s, 1H), 7.48 (d, 1H, J =8.0Hz), 7.38-7.34 (m, 2H), 7.15- 7.12 (m, 2H), 7.01-0.95 (m, 2H), 4.14-4.11 (m, 1H), 3.93 (s, 3H), 2.22-1.19 (m, 1H), 1.12-1.10 (m, 6H), 0.64 (d, 3H, J =6.4 Hz).

Example 123

6-chloro-5'-(3-chlorophenyl)-2'-(2-ethoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(2-ethoxy- 4-Methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (S-122) 38.8 mg; (R)-6-chloro-5'-(3-chlorophenyl)-2'-(2-ethoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro 38.7 mg of [dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-122) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₄ Cl ₂ N ₆ O ₄ 578.12, m/z found 579.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.33 (brs, 1H), 8.49 (s, 1H), 7.48 (d, 1H, J =8.4Hz), 7.38-7.34 (m, 2H), 7.15- 7.11 (m, 2H), 7.01 (s, 1H), 6.97-6.95 (m, 1H), 4.46 (q, 2H, J =7.2Hz), 4.19-4.14 (m, 1H), 3.93 (s, 3H) , 1.39 (t, 3H, J =7.2Hz), 1.12 (d, 3H, J =6.8Hz), 0.65 (d, 3H, J =6.4Hz).

Example 124

6-chloro-5'-(3-chlorophenyl)-2'-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydro Indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(2-isopropoxy). -4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6 '(5'H)-dione (S-123) 43.9mg; (R)-6-chloro-5'-(3-chlorophenyl)-2'-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H- 45.7 mg of spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-123) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₆ C _l2 N ₆ O ₄ 592.14, m/z found 593.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.58 (brs, 1H), 8.48 (s, 1H), 7.48-6.96 (m, 7H), 5.32-5.26 (m, 1H), 4.20-4.14 (m , 1H), 2.31 (s, 3H), 1.38 (d, 6H, J =6.0Hz), 1.13 (d, 3H, J =6.8Hz), 0.65 (d, 3H, J =6.8Hz).

Example 125

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-(dimethylamino)-5-ethyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro [Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain 6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-(dimethylamino) -5-ethyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6' 53.23 mg of (5'H)-dione was obtained. MS (ESI): mass calcd. for C ₃₃ H ₃₃ C _l2 N ₅ O ₃ 617.20, m/z found 618.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.47 (brs, 1H), 7.95-6.47 (m, 8H), 4.11-4.08 (m, 1H), 3.78 (s, 3H), 2.74 (s, 6H) ), 2.66-2.61 (m, 2H), 2.22 (s, 3H), 1.238-1.071 (m, 6H), 0.68 (d, 3H, J =6.4Hz).

Example 126

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro [Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2- Isopropoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]- 2,6'(5'H)-dione (S-126) 28.9 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3 35.5 mg of'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-126) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₈ Cl ₂ N ₆ O ₄ 606.15, m/z found 607.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.76 (brs, 1H), 8.50 (d, 1H, J =6.4Hz), 7.57-6.49 (m, 6H), 5.32-5.26 (m, 1H), 4.20-4.16 (m, 1H), 3.94 (s, 3H), 2.22 (s, 3H), 1.38 (d, 6H, J =6.0Hz), 1.09 (d, 3H, J =4.4Hz), 0.67 (d , 3H, J =6.0Hz).

Example 127

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-ethoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2- Ethoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-127) 27.9mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-ethoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3' 32.0 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-127) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₆ Cl ₂ N ₆ O ₄ 592.14, m/z found 593.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.75 (brs, 1H), 8.52 (d, 1H, J =6.8Hz), 7.567-6.486 (m, 6H), 4.46 (q, 2H, J =7.2 Hz), 4.18-4.09 (m, 1H), 3.94 (s, 3H), 2.21 (s, 3H), 1.39 (t, 3H, J =7.2Hz), 1.09 (d, 3H, J =4.8Hz), 0.67 (d, 3H, J =6.0 Hz).

Example 128

4-(6-Chloro-5'-(3-chlorophenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[dihydroindole- 3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-3-methoxybenzonitrile

The title compound was obtained following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-4-(6-chloro-5'-(3-chlorophenyl)-3'-isopropyl- 2,6'-dioxo-5',6'-dihydro-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl) 35.3 mg of -3-methoxybenzonitrile (S-128); (R)-4-(6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[ 34.5 mg of dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-3-methoxybenzonitrile (R-128) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₁ Cl ₂ N ₅ O ₃ 557.10, m/z found 558.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.43 (brs, 1H), 7.73-6.96 (m, 10H), 4.06-4.04 (m, 1H), 3.86 (s, 3H), 1.04 (d, 3H) , J =5.6Hz), 0.61 (d, 3H, J =5.6Hz).

Example 129

6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'-(2-methoxy-4-(trifluoromethyl)phenyl)-3'H-spiro[dihydroindole- 3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to (S)-6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'- (2-methoxy-4-(trifluoromethyl)phenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'( 40.2 mg of 5'H)-dione (S-129); (R)-6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'-(2-methoxy-4-(trifluoromethyl)phenyl)-3'H-spiro[ 44.7 mg of dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-129) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₁ Cl ₂ F ₃ N ₄ O ₃ 600.1, m/z found 601.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.56 (brs, 1H), 7.68-6.95 (m, 10H), 4.07-4.04 (m, 1H), 3.88 (s, 3H), 1.10 (d, 3H) , J =6.0Hz), 0.62 (d, 3H, J =6.0Hz).

Example 130

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-fluoro-4,6-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole -3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2- Fluoro-4,6-dimethoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (S-130) 42.7mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-fluoro-4,6-dimethoxyphenyl)-3'-isopropyl-3'H-spiro 30.0 mg of [dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-130) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₅ Cl ₂ FN ₄ O ₄ 594.12, m/z found 595.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.75 (brs, 1H), 7.44-6.60 (m, 8H), 4.00 (s, 1H), 3.86-3.77 (m, 6H), 3.86 (s, 3H) ), 3.81 (d, 3H, J =2.8Hz), 2.22(s, 3H), 1.23-1.01 (m, 3H), 0.69-0.61 (m, 3H).

Example 131

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro [Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(4,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]- 45.5 mg of 2,6'(5'H)-dione (S-131); (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-isopropyl-3 50.5 mg of'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-131) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₄ Cl ₂ N ₆ O ₄ 578, m/z found 579.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.80 (brs, 1H), 8.50 (d, 1H, J =1.6Hz), 8.48 (d, 1H, J =2.0Hz), 8.14-7.00 (m, 4H), 6.60 (s, 1H), 4.09-4.06 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.27 (s, 3H), 1.08 (d, 3H, J =4.0Hz ), 0.65 (d, 3H, J =4.0 Hz).

Example 132

5-(6-Chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxypyridylmethylcyanide

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-5-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'- Isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2' -Yl)-4-methoxypyridylmethyl cyanide (S-132) 4.9mg; (R)-5-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H -Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxypyridylmethylcyanide (R-132) 5.4mg was obtained. . MS (ESI): mass calcd. for C ₂₉ H ₂₂ Cl ₂ N ₆ O ₃ 572.11, m/z found 573.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.36 (brs, 1H), 8.69 (d, 1H, J =6.8Hz), 8.06 (s, 1H),7.57-6.99 (m, 6H), 4.12- 4.10 (m, 1H), 3.97 (s, 3H), 2.21 (s, 3H), 1.08 (d, 3H, J =7.6Hz), 0.65 (d, 3H, J =7.6Hz).

Example 133

6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydro Indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-( 4,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6 63.3 mg of'(5'H)-dione (S-133); (R)-6-chloro-5'-(5-chloro-2-fluorophenyl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H- 66.9 mg of spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-133) was obtained. MS (ESI): mass calcd. for Chemical Formula: C ₂₈ H ₂₂ Cl ₂ FN ₅ O ₄ 581.10, m/z found 582.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.57 (brs, 1H), 8.13 (s, 1H), 7.48 (d, 1H, J =7.2Hz), 7.36-7.32 (m, 2H), 7.15 ( d, 1H, J =8.0Hz), 7.06 (d, 1H, J =3.6Hz), 7.05 (s, 1H), 6.59 (s, 1H), 4.09-4.05 (m, 1H), 3.92 (s, 3H ), 3.84 (s, 3H), 1.10 (d, 3H, J =6.4Hz), 0.64 (d, 3H, J =6.4Hz).

Example 134

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2-ethoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3 'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(2-ethoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d] Imidazole]-2,6'(5'H)-dione (S-134) 38.8 mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2-ethoxy-4-methoxypyrimidin-5-yl)-3'- 40.0 mg of isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-134) Obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₅ Cl ₂ N ₇ O ₄ 593, m/z found 594.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.79 (brs, 1H), 8.52-8.48 (m, 2H), 7.64-7.00 (m, 4H), 4.47 (q, 2H, J =6.8Hz), 4.21-4.18 (m, 1H), 3.99 (s, 3H), 2.27 (s, 3H), 1.39 (t, 3H, J =6.8Hz), 1.09 (d, 3H, J =6.4Hz), 0.68 (d , 3H, J =6.4Hz).

Example 135

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3'-isopropyl -3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4- d]imidazole]-2,6'(5'H)-dione (S-135) 50.6mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3 '-Isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-135) 50.9 mg was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₆ Cl ₂ N ₈ O ₃ 592, m/z found 593.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.77 (brs, 1H), 8.50 (d, 1H, J =7.2Hz), 8.26 (d, 1H, J =5.2Hz), 7.62-6.99 (m, 4H), 4.17-4.14 (m, 1H), 3.90 (s, 3H), 3.19 (s, 6H), 2.26 (s, 3H), 1.09 (d, 3H, J =6.4Hz), 0.68 (d, 3H , J =6.4Hz).

Example 136

6-Chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl- 3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d ]Imidazole]-2,6'(5'H)-dione (S-136) 33.0mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3'-Isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-136) 30.5mg Was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₈ Cl ₂ N ₆ O ₄ 606 m/z found 607.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.79 (brs, 1H), 8.51 (m, 2H), 7.63-7.00 (m, 4H), 5.32-5.28 (m, 1H), 4.22-4.16 (m , 1H), 3.94 (s, 3H), 2.27 (s, 3H), 1.37 (d, 6H, J =6.4Hz), 1.09 (d, 3H, J =6.4Hz), 0.68 (d, 3H, J = 6.4Hz).

Example 137

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(6-isopropoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3 'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(6-isopropoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d] Imidazole]-2,6'(5'H)-dione (S-137) 30.9mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(6-isopropoxy-4-methoxypyridin-3-yl)-3'- Isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-137) 32.3mg Obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₈ Cl ₂ N ₆ O ₄ 606, m/z found 607.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.77 (brs, 1H), 8.50 (d, 1H, J =6.8Hz), 8.11 (d, 3H, J =6.4Hz), 7.64-7.00 (m, 4H), 6.52 (s, 1H), 5.35-5.32 (m, 1H), 4.10-4.07 (m, 1H), 3.83 (s, 3H), 2.27 (s, 3H), 1.33 (d, 6H, J = 6.0Hz), 1.08 (d, 3H, J =6.4Hz), 0.66 (d, 3H, J =6.4Hz).

Example 138

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3'H -Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole ]-2,6'(5'H)-dione (S-138) 42.6mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl) -3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-138) 40.9mg was obtained. . MS (ESI): mass calcd. for C ₂₉ H ₂₂ Cl ₂ F ₃ N ₅ O ₃ 615.10, m/z found 616.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.75 (brs, 1H), 8.72 (d, 1H, J =6.8Hz), 7.74 (s, 1H),7.59-6.49 (m, 6H), 4.20- 4.11 (m, 1H), 4.02 (s, 3H), 2.22 (s, 3H), 1.18 (d, 3H, J =6.4Hz), 0.66 (d, 3H, J =6.4Hz).

Example 139

6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-(6-ethoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro [Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-( 6-Ethoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]- 45.7 mg of 2,6'(5'H)-dione (S-139); (R)-6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-(6-ethoxy-4-methoxypyridin-3-yl)-3'-isopropyl-3 42.1 mg of'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-139) was obtained. MS (ESI): mass calcd. for Chemical Formula: C ₂₉ H ₂₄ Cl ₂ FN ₅ O ₄ Exact Mass: 595.12, m/z found 596.5 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.58 (brs, 1H), 8.08 (s, 1H), 7.49 (d, 1H, J =8.0Hz), 7.38 (d, 1H, J =8.4Hz) , 7.16 (d, 1H, J =7.6Hz), 7.06 (s, 1H), 6.96 (s, 1H), 6.92 (d, 1H, J =9.6Hz), 6.56 (s, 1H), 4.40 (q, 2H, J =6.8Hz), 4.07-4.02 (m, 1H), 3.83 (s, 3H), 1.35 (t, 3H, J =6.8Hz), 1.11 (d, 3H, J =5.6Hz), 0.62 ( d, 3H, J =6.0 Hz).

Example 140

6-Chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3'-isopropyl- 3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2- (2-Fluoroethoxy)-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d ]Imidazole]-2,6'(5'H)-dione (S-140) 36.1mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3'-Isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-140) 31.5mg Was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₅ Cl ₂ FN ₆ O ₄ 610.13, m/z found 611.4 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ): δ 11.50 (brs, 1H), 8.539 (d, J = 7.2 Hz, 1H), 7.57-6.48 (m, 6H), 4.86-4.61 (m, 4H) , 4.19-4.16 (m, 1H), 3.96 (s, 3H), 2.145 (s, 3H), 1.09 (d, J = 4.8 Hz, 3H), 0.66 (d, J = 6.0 Hz, 3H).

Example 141

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxy-2-(2,2,2-trifluoroethoxy)pyrimidine- 5-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(4-methoxy-2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[ 3,4-d]imidazole]-2,6'(5'H)-dione (S-141) 36.4 mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxy-2-(2,2,2-trifluoroethoxy) )Pyrimidin-5-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R -141) 43.1 mg was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₁ C _l2 F ₃ N ₆ O ₄ 646.11, m/z found 649.1 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.45 (brs, 1H), 8.60 (d, J = 7.6 Hz, 1H), 7.56-6.49 (m, 6H), 5.15-5.01 (m, 2H), 4.21-4.15 (m, 1H), 3.99 (s, 3H), 2.07 (s, 3H), 1.08 ( d, J = 6.4 Hz, 3H), 0.66 (d, J = 6.4 Hz, 3H).

Example 142

6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to (S)-6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'- (4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-142) 20.9mg; (R)-6-chloro-5'-(3-chlorophenyl)-3'-isopropyl-2'-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3' 21.6 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-142) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₀ Cl ₂ F ₃ N ₅ O ₃ 601.08, m/z found 602.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.56 (brs, 1H), 8.69 (s, 1H), 7.73 (s, 1H), 7.51 (d, 1H, J =8.8Hz), 7.39-7.35 ( m, 2H), 7.16-7.01 (m, 2H), 6.98-6.97 (m, 2H), 4.13-4.08 (m, 1H), 4.01 (s, 3H), 1.12 (d, 3H, J =6.4Hz) , 0.64 (d, 3H, J =6.4 Hz).

Example 143

6-Chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(6-cyclopropyl-4-methoxypyridin-3-yl)-3'-isopropyl-3' H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(6-cyclopropyl-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d] already Dazole]-2,6'(5'H)-dione (S-143) 23.6mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(6-cyclopropyl-4-methoxypyridin-3-yl)-3'-iso 23.8 mg of propyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-143) was obtained. I did. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₆ O ₃ 588, m/z found 589.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.76 (brs, 1H), 8.50 (d, 1H, J =8.0Hz), 8.30 (d, 1H, J =3.6Hz), 7.64-6.99 (m, 5H), 4.09-4.05 (m, 1H), 3.88 (s, 3H), 2.27 (s, 3H), 2.19-2.17 (m, 1H), 1.08 (d, 3H, J =6.4Hz), 1.02-1.00 (m, 4H), 0.65 (d, 3H, J =4.0 Hz).

Example 144

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-3'-isopropyl-2'-(2-methoxy-4-(trifluoromethyl)phenyl)-3' H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-3. '-Isopropyl-2'-(2-methoxy-4-(trifluoromethyl)phenyl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d] already Dazole]-2,6'(5'H)-dione (S-144) 40.9mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-3'-isopropyl-2'-(2-methoxy-4-(trifluoromethyl)phenyl )-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-144) 47.4mg was obtained I did. MS (ESI): mass calcd. for C ₂₉ H ₂₂ Cl ₂ F ₃ N ₅ O ₃ 615, m/z found 616.4[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.79 (brs, 1H), 8.51 (d, 1H, J =7.6Hz), 7.71-7.00 (m, 7H), 4.10-4.07 (m, 1H), 3.90 (s, 3H), 2.28 (s, 3H), 1.07 (d, 3H, J =5.2Hz), 0.66 (d, 3H, J =5.6Hz).

Example 145

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(4-cyclopropyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(4-cyclopropyl-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 23.3mg, 6'(5'H)-dione (S-145); (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(4-cyclopropyl-2-methoxyphenyl)-3'-isopropyl-3' 21.9 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-145) was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₇ Cl ₂ N ₅ O ₃ 587, m/z found 588.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.71 (brs, 1H), 8.50 (d, 1H, J =7.6Hz), 7.62-6.78 (m, 7H), 4.09-4.06 (m, 1H), 3.78 (s, 3H), 2.27 (s, 3H), 2.01-1.99 (m, 1H), 1.06-1.01 (m, 5H), 0.85-0.80 (m, 2H), 0.62 (d, 3H, J =5.6 Hz).

Example 146

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-ethoxy-2-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6- Ethoxy-2-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2, 17.2 mg of 6'(5'H)-dione (S-146); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-ethoxy-2-methoxypyridin-3-yl)-3'-isopropyl-3'H 21.7 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-146) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₇ Cl ₂ N ₅ O ₄ 591.14, m/z found 592.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.55 (brs, 1H), 7.81-6.48 (m, 8H), 4.42 (q, 2H, J =7.2Hz), 4.13-4.11 (m, 1H), 3.88 (s, 3H), 2.22 (s, 3H), 1.38 (t, 3H, J =7.2Hz), 1.08 (d, 3H, J =6.4Hz), 0.66 (d, 3H, J =6.8Hz).

Example 147

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-3'- Isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2- (2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3, 4-d]imidazole]-2,6'(5'H)-dione (S-147) 52.3mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl) -3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-147 ) 48.2mg was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₄ Cl ₂ F ₂ N ₆ O ₄ 628.12, m/z found 629.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 8.58 (d, 1H, J =7.2Hz), 7.56-6.46 (m, 7H), 4.74-4.66 (m, 2H), 4.17-4.10 (m, 1H) ), 3.98 (s, 3H), 2.21 (s, 3H), 2.01-1.98 (m, 1H), 1.09 (d, 3H, J =6.8 Hz), 0.68 (d, 3H, J =7.2 Hz).

Example 148

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro [Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4- (2-hydroxyethoxy)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]- 43.3 mg of 2,6'(5'H)-dione (S-148); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-3'-isopropyl-3 43.7 mg of'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-148) was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₈ Cl ₂ N ₄ O ₅ 606.14, m/z found 607.2 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.55-6.48 (m, 10H), 4.89 (t, J = 5.2 Hz, 1H), 4.10-4.05 (m, 3H), 3.78-3.74 (m, 5H), 2.07 (s, 3H), 1.06 (d, J = 5.6 Hz, 3H), 0.63 (d, J = 5.6 Hz, 3H).

Example 149

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(6-isopropyl-2-methoxypyridin-3-yl)-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(6-isopropyl-2-methoxypyridin-3-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2, 16.3 mg of 6'(5'H)-dione (S-149); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(6-isopropyl-2-methoxypyridin-3-yl)-3'H 17.0 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-149) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₃₁ Cl ₂ N ₅ O ₃ 589.16, m/z found 589.5[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.72 (brs, 1H), 7.84-7.81 (m, 1H), 7.57 (d, 1H, J =8.0Hz), 7.47 (d, 1H, J =8.0 Hz), 7.33-6.97 (m, 4H), 6.49 (s ,1H), 4.10-4.07 (m, 1H), 3.89 (s, 3H), 3.04-3.01 (m, 1H), 2.22 (s, 3H) , 1.29 (d, 6H, J =6.8Hz), 1.10 (d, 1H, J =6.8Hz), 0.66 (d, 1H, J =6.8Hz).

Example 150

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-(difluoromethoxy)-4-methoxypyridin-3-yl)-3'-isopropyl-3'H -Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6- (Difluoromethoxy)-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole ]-2,6'(5'H)-dione (S-150) 42.1mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-(difluoromethoxy)-4-methoxypyridin-3-yl)-3'-isopropyl -3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-150) 46.0 mg was obtained. . MS (ESI): mass calcd. for C ₂₉ H ₂₃ Cl ₂ F ₂ N ₅ O ₄ 613.11, m/z found 614.5 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.65 (brs, 1H), 8.25-6.48 (m, 8H), 4.09-4.07 (m, 1H), 3.91 (s, 3H), 2.22 (s, 3H) ), 1.08 (d, 3H, J =6.4Hz), 0.66 (d, 3H, J =6.4Hz).

Example 151

4-Chloro-2-(6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-2,6'-dioxo-3',6'- Dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-5'-yl)benzonitrile

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-4-chloro-2-(6-chloro-2'-(2,4-dimethoxypyrimi). Din-5-yl)-3'-isopropyl-2,6'-dioxo-3',6'-dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3, 119.4 mg of 4-d]imidazole]-5'-yl)benzonitrile (S-151); (R)-4-chloro-2-(6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-2,6'-dioxo-3',6'-dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-5'-yl)benzonitrile (R-151) 105.8mg Obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₁ Cl ₂ N ₇ O ₄ 589.10, m/z found 590.1 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.81 (brs, 1H), 8.56 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H ), 7.56-7.53 (m, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 7.09-7.07 (m, 1H), 4.24-4.17 (m, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 1.21 (d, J = 6.4 Hz, 3H), 0.63 (d, J = 6.4 Hz, 3H).

Example 152

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-3'-isopropyl-2'-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl )-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-3. '-Isopropyl-2'-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4 -d]imidazole]-2,6'(5'H)-dione (S-152) 41.8 mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-3'-isopropyl-2'-(4-methoxy-6-(trifluoromethyl)pyridine -3-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-152) 45.3 mg were obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₁ Cl ₂ F ₃ N ₆ O ₃ 616 m/z found 617.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.57 (brs, 1H), 8.72 (d, 1H, J =7.2Hz), 8.51 (d, 1H, J =6.4Hz), 7.74 (s, 1H) , 7.66-7.01 (m, 5H), 4.16-4.11 (m, 1H), 4.02 (s, 3H), 2.27 (s, 3H), 1.10 (d, 3H, J =6.8Hz), 0.67 (d, 3H , J =6.4Hz).

Example 153

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-(2,2-difluoroethoxy)-4-methoxypyridin-3-yl)-3'-iso Propyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6- (2,2-Difluoroethoxy)-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4 -d]imidazole]-2,6'(5'H)-dione (S-153) 45.1mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-(2,2-difluoroethoxy)-4-methoxypyridin-3-yl)- 3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-153) 46.6 mg was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₅ Cl ₂ F ₂ N ₅ O ₄ 627.12, m/z found 628.2[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.73 (brs, 1H), 8.16 (d, 1H, J =5.2Hz) ,7.57-6.42 (m, 7H), 4.68-4.61 (m, 2H), 4.08-4.04 (m, 1H), 3.87 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J =6.4Hz), 0.65 (d, 3H, J =6.4Hz).

Example 154

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxy-6-methylpyridin-3-yl)-3'H-spiro[dihydro Indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(4-methoxy-6-methylpyridin-3-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6 39.3 mg of'(5'H)-dione (S-154); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(4-methoxy-6-methylpyridin-3-yl)-3'H- 39.5 mg of spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-154) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₅ Cl ₂ N ₅ O ₃ 561.13, m/z found 562.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.73 (brs, 1H), 8.35 (d,1H, J =4.4Hz), 7.57-6.48 (m, 7H), 4.07-4.03 (m, 1H), 3.87 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J =6.8 Hz), 0.64 (d, 3H, J =6.4 Hz).

Example 155

6-Chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3'-isopropyl- 3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d ]Imidazole]-2,6'(5'H)-dione (S-155) 9.1mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3'-Isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-155) 9.9mg Was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₇ Cl ₂ N ₇ O ₃ 591.16, m/z found 594.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.79 (brs, 1H), 8.50 (s, 1H), 8.49 (d, 1H, J =5.6Hz), 7.99-6.99 (m, 4H), 6.22 ( s, 1H), 4.11-4.08 (m, 1H), 3.84 (s, 3H), 3.11 (s, 6H), 2.27 (s, 3H), 1.08 (d, 3H, J =6.4Hz), 0.65 (d , 3H, J =4.0Hz).

Example 156

6-chloro-5'-(5-chloro-2-isopropylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain 6-chloro-5'-(5-chloro-2-isopropylphenyl)-2'-(2,4- Dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'( 50.95 mg of 5'H)-dione was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₈ Cl ₂ N ₆ O ₄ 606.15, m/z found 607.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 8.53 (d, 1H, J =6.0Hz), 7.65-7.07 (m, 6H), 4.13-4.06 (m, 1H), 3.99 (d, 3H, J) =13.6Hz), 3.96 (d, 3H, J =13.6Hz), 3.17-3.16 (m, 1H), 1.15-1.03 (m, 9H), 0.63 (d, 3H, J =5.6Hz).

Example 157

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-(dimethylamino)-2-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro [Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6- (Dimethylamino)-2-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]- 16.2 mg of 2,6'(5'H)-dione (S-157); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-(dimethylamino)-2-methoxypyridin-3-yl)-3'-isopropyl-3 17.6 mg of'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-157) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₈ Cl ₂ N ₆ O ₃ 590.16, m/z found 591.1 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.60 (brs, 1H), 7.58-6.29 (m, 8H), 4.21-4.14 (m, 1H), 3.83 (s, 3H), 3.09 (s, 6H), 2.14 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H), 0.64 (d, J = 6.8 Hz, 3H).

Example 158

2-Chloro-4-(6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-2,6'-dioxo-3',6'- Dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-5'-yl)benzonitrile

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-2-chloro-4-(6-chloro-2'-(2,4-dimethoxypyrimi). Din-5-yl)-3'-isopropyl-2,6'-dioxo-3',6'-dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3, 119.4 mg of 4-d]imidazole]-5'-yl)benzonitrile (S-158); (R)-2-chloro-4-(6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-2,6'-dioxo-3',6'-dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-5'-yl)benzonitrile (R-158) 105.8mg Obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₁ Cl ₂ N ₇ O ₄ 589.10, m/z found 590.1 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.81 (brs, 1H), 8.52 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H ), 7.47 (d, J = 8.0 Hz, 1H), 7.17-7.09 (m, 3H), 4.20-4.13 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.13 (d, J = 6.8 Hz, 3H), 0.61 (d, J = 6.8 Hz, 3H).

Example 159

6-Chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3'-isopropyl-3 'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d] Imidazole]-2,6'(5'H)-dione (S-159) 55.9mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3'- 55.7 mg of isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-159) Obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₆ O ₃ 589.14, m/z found 590.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.65 (brs, 1H), 8.56-7.00 (m, 6H), 4.17-4.14 (m, 1H), 3.94 (s, 3H), 2.27 (s, 3H) ), 2.20-2.19 (m, 1H), 1.13-1.07 (m, 7H), 0.68 (d, 3H, J =6.8 Hz).

Example 160

3-Chloro-5-(6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-2,6'-dioxo-3',6'- Dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-5'-yl)benzonitrile

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-3-chloro-5-(6-chloro-2'-(2,4-dimethoxypyrimi). Din-5-yl)-3'-isopropyl-2,6'-dioxo-3',6'-dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3, 20.4 mg of 4-d]imidazole]-5'-yl)benzonitrile (S-160); (R)-3-chloro-5-(6-chloro-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-2,6'-dioxo-3',6'-dihydro-5'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-5'-yl)benzonitrile (R-160) 23.3mg Obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₁ Cl ₂ N ₇ O ₄ 589.10, m/z found 590.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.71 (brs, 1H), 8.52 (s, 1H), 7.98 (s, 1H), 7.51-7.45 (m, 3H), 7.18-7.16 (m, 1H) ), 7.08 (s, 1H), 4.17-4.16 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.12 (d, 3H, J =5.2Hz), 0.64 (d, 3H, J =4.8Hz).

Example 161

6-chloro-5'-(3-chloro-4-(trifluoromethoxy)phenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3' H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

Following similar steps as in Example 1 to obtain the title compound, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(3-chloro-4-(trifluoromethoxy)phenyl)- 2'-(2,4-dimethoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d] already Dazole]-2,6'(5'H)-dione (S-161) 20.4mg; (R)-6-chloro-5'-(3-chloro-4-(trifluoromethoxy)phenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-iso 23.3 mg of propyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-161) was obtained. I did. MS (ESI): mass calcd. for C ₂₈ H ₂₁ Cl ₂ F ₃ N ₆ O ₅ 648.09, m/z found 649.1 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.63 (brs, 1H), 8.52 (s, 1H), 7.61-7.50 (m, 2H), 7.38 (d, J =2.4 Hz, 1H), 7.18-7.05 (m, 3H), 4.20-4.13 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.11 (d, J = 6.8 Hz, 3H) , 0.64 (d, J = 6.8 Hz, 3H).

Example 162

6-Chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxyphenyl)-3'-isopropyl- 3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4- ((2-hydroxyethyl)(methyl)amino)-2-methoxyphenyl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d ]Imidazole]-2,6'(5'H)-dione (S-162) 16.7mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxyphenyl)-3'-Isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-162) 16.7mg Was obtained. MS (ESI): mass calcd. for C ₃₂ H ₃₁ Cl ₂ N ₅ O ₄ , 619.18 m/z found 620.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.80 (brs, 1H), 7.51-6.34 (m, 9H), 4.72 (t, 1H, J =5.0Hz), 4.13-4.10 (m, 1H), 3.76(s, 3H),3.60-3.57 (m, 2H), 3.49-3.47 (m, 2H), 3.02 (s, 3H), 2.22 (s, 3H), 1.05 (d, 3H, J =6.0Hz) , 0.62 (d, 3H, J =5.6 Hz).

Example 163

6-Chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3'-isopropyl-3 'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained according to steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6- (2-Fluoroethoxy)-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d] Imidazole]-2,6'(5'H)-dione (S-163) 12.4mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3'- 12.4 mg of isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-163) Obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ FN ₅ O ₄ 609.13, m/z found 610.1[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.73 (brs, 1H), 8.13 (d, 1H, J =4.8Hz ), 7.54-6.91 (m, 6H), 6.67 (s,1H), 4.83- 4.54 (m, 4H), 4.07-4.06 (m, 1H), 3.86 (s, 3H), 2.21 (s, 3H), 1.08 (d, 3H, J =6.0Hz), 0.65 (d, 3H, J = 6.0Hz).

Example 164

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(6-isopropyl-4-methoxypyridin-3-yl)-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(6-isopropyl-4-methoxypyridin-3-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2, 14.4 mg of 6'(5'H)-dione (S-164); (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(6-isopropyl-4-methoxypyridin-3-yl)-3'H 14.5 mg of -spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-164) was obtained. MS (ESI): mass calcd. for C ₃₁ H ₂₉ Cl ₂ N ₅ O ₃ , 589.16 m/z found 590.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.5 (brs, 1H), 8.43 (d, 1H, J =4.8Hz), 7.59-6.49 (m, 7H), 4.11-4.02 (m,1H), 3.91(s, 3H), 3.12-3.09 (m, 1H), 2.22 (s, 3H), 1.30-1.29 (m, 6H), 1.07 (d, 3H, J =6.8Hz), 0.65 (d, 3H, J =6.8 Hz).

Example 165

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxyphenyl)-3'-(1-hydroxypropan-2-yl)-3'H-spiro [Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

Following steps similar to Example 1, the title compound 6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxyphenyl)-3'-(1-hydroxypropane- 2-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione 20.0mg was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₆ Cl ₂ N ₄ O ₅ 592.13, m/z found 593.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 10.80 (brs, 1H), 9.35 (s, 1H), 7.59-6.71 (m, 9H), 4.33-4.29 (m, 2H), 3.93-3.85 (m) , 7H), 2.07 (s, 3H), 1.18 (d, J = 6.0 Hz, 3H).

Example 166

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-3'-isopropyl-2'-(6-isopropyl-4-methoxypyridin-3-yl)-3' H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-3. '-Isopropyl-2'-(6-isopropyl-4-methoxypyridin-3-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d] already Dazole]-2,6'(5'H)-dione (S-166) 31.8mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-3'-isopropyl-2'-(6-isopropyl-4-methoxypyridin-3-yl )-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-166) 33.1mg was obtained I did. MS (ESI): mass calcd. for C ₃₀ H ₂₈ Cl ₂ N ₆ O ₃ , 590.16 m/z found 591.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.59 (brs, 1H), 8.51-8.41 (m,2H), 7.67-7.01 (m, 5H), 4.12-4.05 (m,1H), 3.90 (s , 3H), 3.11-3.06 (m, 1H), 2.50 (s, 3H), 1.30 (d, 6H, J =6.8Hz), 1.09 (d, 3H, J =6.4Hz), 0.66 (d, 3H, J =4.0Hz).

Example 167

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-(1-hydroxymethylpropan-2-yl )-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

Following steps similar to Example 1, the title compound 6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(2,4-dimethoxypyrimidin-5-yl)-3'-( 1-hydroxymethylpropan-2-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)- 50.6 mg of dione was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₄ Cl ₂ N ₆ O ₅ 594.12, m/z found 595.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 10.80 (brs, 1H), 9.43 (s, 1H), 8.66 (s, 1H), 7.50 (s, 1H), 7.50-6.88 (m, 5H), 4.40-4.31 (m, 2H), 4.02 (s, 6H), 3.93 (d, J = 12.0 Hz), 2.05 (s, 3H), 1.24 (s, 3H).

Example 168

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-(1-hydroxypropan-2-yl)-3 'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

Following similar steps as in Example 1 the title compound 6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-(1- Hydroxypropan-2-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione 101.2mg Was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₅ Cl ₂ N ₅ O ₅ 593.12, m/z found 594.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 10.83 (brs, 1H), 9.42 (s, 1H), 8.25 (s, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.28-6.88 ( m, 6H), 6.64 (s, 1H), 4.34-4.30 (m, 2H), 3.94-3.91 (m, 7H), 2.06 (s, 3H), 1.21 (d, 6.8 Hz, 3H).

Example 169

6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-ethoxy-4-methoxypyridin-3-yl)-3'-(1-hydroxypropan-2-yl )-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

Following similar steps to Example 1, the title compound 6-chloro-5'-(5-chloro-2-methylphenyl)-2'-(6-ethoxy-4-methoxypyridin-3-yl)-3'- (1-hydroxypropan-2-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)- 151.1 mg of dione was obtained. MS (ESI): mass calcd. for C ₂₇ H ₂₂ Cl ₂ N ₆ O ₃ 607.14, m/z found 608.1 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.83 (brs, 1H), 9.41 (s, 1H), 8.23 (s, 1H), 7.53 (d, J =2.4 Hz, 1H), 7.28-6.89 (m, 5H), 6.62 (s, 1H), 4.42-4.30 (m, 4H), 3.93-3.90 (m, 4H), 2.06 (s, 3H), 1.36 (t, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H).

Example 170

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3 '-Isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[ 3,4-d]imidazole]-2,6'(5'H)-dione (S-170) 25.2 mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(2-(2-fluoroethoxy)-4-methoxypyrimidine-5- Il)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R -170) 25.9 mg was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₄ Cl ₂ FN ₇ O ₄ 611.12, m/z found 612.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.65 (brs, 1H), 8.56-8.49 (m, 2H), 7.64-7.00 (m, 4H), 4.87-4.85 (m, 1H), 4.75-4.73 (m, 1H), 4.69 -4.67 (m, 1H), 4.61-4.59 (m, 1H), 4.19-4.18 (m, 1H), 3.96 (s, 3H), 2.27 (s, 3H), 1.09 (d , 3H, J =6.8 Hz), 0.68 (d, 3H, J =5.6 Hz).

Example 171

6-chloro-5'-(3-chlorophenyl)-2'-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H -Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(2-(2- Fluoroethoxy)-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole ]-2,6'(5'H)-dione (S-171) 5.3mg; (R)-6-chloro-5'-(3-chlorophenyl)-2'-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3'-isopropyl 4.3 mg of -3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-171) was obtained. . MS (ESI): mass calcd. for C ₂₈ H ₂₃ Cl ₂ FN ₆ O ₄ , 596.11 m/z found 597.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.59 (brs, 1H), 8.52 (s, 1H), 7.49 (d, 1H, J =8.0Hz), 7.38-7.35 (m, 2H), 7.15- 7.12 (m, 2H), 7.01 (d, 1H, J =2.0Hz), 6.98-6.95 (m, 1H), 4.87-4.59 (m, 4H), 4.18-4.15 (m, 1H), 3.95 (s, 3H), 1.12 (d, 3H, J =6.8 Hz), 0.65 (d, 3H, J =6.8 Hz).

Example 172

6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-isopropyl-4-methoxypyrimidin-5-yl)-3'H-spiro[ Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography (S)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl- 2'-(2-isopropyl-4-methoxypyrimidin-5-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2 ,6'(5'H)-dione (S-172) 19.6mg; (R)-6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2'-(2-isopropyl-4-methoxypyrimidin-5-yl)-3' 18.1 mg of H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-172) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₈ Cl ₂ N ₆ O ₃ 590.19, m/z found 591.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.78 (brs, 1H), 8.67 (d, 1H, J =6.4Hz), 8.29-6.48 (m, 6H), 4.08-4.06 (m, 1H), 3.98 (s, 3H), 3.14-3.11 (m, 1H), 2.22 (s, 3H), 1.34 (d, 6H, J =6.8Hz), 1.10 (d, 3H, J = 6.4Hz), 0.68 (d , 3H, J =6.8 Hz).

Example 173

6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3' -Isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and subjected to supercritical high pressure preparative chromatography to obtain (S)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2. '-(6-(2-Fluoroethoxy)-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3 ,4-d]imidazole]-2,6'(5'H)-dione (S-173) 20.1mg; (R)-6-chloro-5'-(5-chloro-2-methylpyridin-3-yl)-2'-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl )-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R- 173) 19.6 mg was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₅ Cl ₂ FN ₆ O ₄ 610.12, m/z found 611.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.81 (brs, 1H), 8.51 (dd, 1H, J ¹ =8.4Hz, J ² =2.4Hz), 8.14 (d, 1H, J =5.6Hz), 7.62-7.00 (m, 4H), 6.69 (s, 3H), 4.84-4.82 (m, 1H), 4.72-4.70 (m, 1H) , 4.63-4.61 (m, 1H), 4.55-4.54 (m, 1H), 4.09-4.07 (m, 1H), 3.86 (s, 3H), 2.27 (s, 3H), 1.08 (d, 3H, J = 6.4Hz), 0.65 (d, 3H, J =6.4Hz).

Example 174

6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H- Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-( 2-cyclopropyl-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole] -2,6'(5'H)-dione (S-174) 37.8 mg; (R)-6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3'-isopropyl- 39.0 mg of 3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-174) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₃ C _l2 FN ₆ O ₃ 592.12, m/z found 593.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.75 (brs, 1H), 8.53 (s, 1H), 7.50 (d, 1H, J =8.0Hz), 7.41-6.89 (m, 5H), 4.17- 4.10 (m, 1H), 3.93 (s, 3H), 2.23-2.17 (m, 1H), 1.12-1.11 (m, 7H), 0.65 (d, 3H, J =6.8Hz).

Example 175

6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydro Indole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-( 4,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6 '(5'H)-dione (S-175) 45.2mg; (R)-6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-isopropyl-3'H- 44.9 mg of spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-175) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₂ Cl ₂ FN ₅ O ₄ 581.10, m/z found 582.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.69 (brs, 1H), 8.11 (s, 1H), 7.50 (d, 1H, J =8.4Hz), 7.48-6.90 (m, 5H), 6.60 ( s, 1H), 4.09-4.02 (m, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 1.11 (d, 3H, J =6.4Hz), 0.61 (d, 3H, J =6.0Hz ).

Example 176

6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-(6-cyclopropyl-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro [Dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-( 6-cyclopropyl-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]- 40.3mg of 2,6'(5'H)-dione (S-176); (R)-6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-(6-cyclopropyl-4-methoxypyridin-3-yl)-3'-isopropyl-3 40.6 mg of'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-176) was obtained. MS (ESI): mass calcd. for C ₃₀ H ₂₄ Cl ₂ FN ₅ O ₃ 591.12, m/z found 592.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.69 (brs, 1H), 8.27 (s, 1H), 7.51 (d, 1H, J =8.4Hz), 7.40-6.80 (m, 6H), 4.09- 4.04 (m, 1H), 3.87 (s, 3H), 2.21-2.07 (m, 1H), 1.11 (d, 3H, J =6.4Hz), 1.10-0.99 (m, 4H), 0.60 (d, 3H, J =6.4Hz).

Example 177

6-Chloro-5'-(3-chlorophenyl)-2'-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3'-isopropyl-3'H- Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following steps similar to Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chlorophenyl)-2'-(6-(2- Fluoroethoxy)-4-methoxypyridin-3-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole] -2,6'(5'H)-dione (S-177) 5.3mg; (R)-6-chloro-5'-(3-chlorophenyl)-2'-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3'-isopropyl- 4.3 mg of 3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-177) was obtained. MS (ESI): mass calcd. for C ₂₉ H ₂₄ Cl ₂ FN ₅ O ₄ 595.12, m/z found 596.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.56 (brs, 1H), 8.11 (s, 1H), 7.49-6.95 (m, 7H), 6.68 (s ,1H), 4.83-4.53 (m, 4H), 4.09-4.02 (m, 1H), 1.11 ( d, 3H, J =6.4 Hz), 0.62 (d, 3H, J =6.4 Hz).

Example 178

6-chloro-5'-(3-chlorophenyl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-(1-hydroxypropan-2-yl)-3'H- Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

Following steps similar to Example 1, the title compound 6-chloro-5'-(3-chlorophenyl)-2'-(4,6-dimethoxypyridin-3-yl)-3'-(1-hydroxypropane -2-yl)-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione 120.1mg was obtained. . MS (ESI): mass calcd. for C ₂₈ H ₂₃ Cl ₂ N ₅ O ₅ 579.11 _, m/z found 580.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 10.88 (brs, 1H), 10.06 (s, 1H), 8.24 (s, 1H), 7.80 (s, 1H), 7.79-6.92 (m, 6H), 6.63 (s, 1H), 4.32-4.29 (m, 2H), 3.94 (s, 6H), 3.92-3.89 (m, 1H), 1.22 (d, 3H, J = 6.8 Hz).

Example 179

5-(6-Chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'-dihydro-3'H-spiro[di Hydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxypyrimidine-2-methylcyanide

Following similar steps to Example 1, the title compound 5-(6-chloro-5'-(5-chloro-2-methylphenyl)-3'-isopropyl-2,6'-dioxo-5',6'- Dihydro-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2'-yl)-4-methoxypyrimidine-2-methylcyanide 4.3 mg was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₁ C _l2 N ₇ O ₃ Exact Mass: 573.11, m/z found 574.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 11.81 (brs, 1H), 8.96 (d, J = 8.4 Hz, 1H), 7.59-6.50 (m, 6H), 4.27-4.22 (m, 1H), 4.05 (s, 3H), 2.21 (s, 3H), 1.10 (d, J =6.8 Hz, 3H), 0.67 (d, J =6.4 Hz, 3H).

Example 180

6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-(2-ethoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H- Spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione

The title compound was obtained by following similar steps as in Example 1, and supercritical high pressure preparative chromatography was performed to obtain (S)-6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-( 2-Ethoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl-3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole] -2,6'(5'H)-dione (S-180) 44.3mg; (R)-6-chloro-5'-(3-chloro-5-fluorophenyl)-2'-(2-ethoxy-4-methoxypyrimidin-5-yl)-3'-isopropyl- 45.1 mg of 3'H-spiro[dihydroindole-3,4'-pyrrolo[3,4-d]imidazole]-2,6'(5'H)-dione (R-180) was obtained. MS (ESI): mass calcd. for C ₂₈ H ₂₃ Cl ₂ FN ₆ O ₄ 596.11, m/z found 597.1 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.69 (brs, 1H), 8.50 (d, J =3.2Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.41-6.90 (m , 5H), 4.47 (q, J =6.8Hz, 2H), 4.21-4.14 (m, 1H), 3.97 (s, 3H), 1.27 (t, J =6.4Hz, 2H), 1.13 (d, J = 6.8 Hz, 3H), 0.64 (d, J = 6.4 Hz, 3H).

In order to verify the activity of the MDM2 inhibitor according to the present invention, the present invention further provides representative test examples.

Test Example 1 Measurement of inhibitory activity against MDM2 of the compound of the present invention by a biological measurement method

Experimental Objective : Measurement of inhibitory activity against MDM2 of the compounds of the present invention

This experiment used the following measurement method/device/reagent:

designation Type (product code) manufacturer Plate shaker MTS2/4 IKA Microplate reader M1000pro TECAN Centrifuge Avanti J-26XP Beckman Coulter GST-MDM2 (70μM) In-house purification Biotin-P53 (100 μM) GL Biochem Anti-GST-Tb(100Х) 61GSTTLA Cisbio SA-XL665 (16.67 μM) 610SAXLA Cisbio BSA B2064 Sigma AEBSF 76307 Sigma DTT 43816 Sigma PBS 20012-027 Cisbio

Subject: Positive control: Compound HDM201, disclosed in Patent 201380016617.6; It was synthesized in the laboratory.

Experimental groups S-1 to R-180, respectively, correspond to the compounds prepared in Examples 1 to 180.

Experimental process:

Preparation of solution:

Buffer: 1ХPBS + 0.1% BSA + 5mM DTT; MDM2 Buffer: Buffer + 1mM AEBSF

GST-MDM2: The final concentration was 4 nM, and should be prepared with 20 nM (5 Х), the mother liquor was diluted 3500 times, first 10 times diluted, and then 350 times diluted.

Biotin-P53: The final concentration is 37nM, and should be prepared with 185nM (5Х), and the mother liquor was diluted 540.5 times.

SA-XL665: The final concentration is 4.625 nM, should be prepared with 1805 nM (4 Х), and the mother liquor was diluted 901 times.

Anti-GST-Tb: The final concentration was 2X, and the mother liquor was diluted 50 times.

MIX: GST-MDM2, Biotin-P53, SA-XL665, and Anti-GST-Tb were uniformly mixed at 4:4:5:5.

Sample: Preparation of sample (10 mM in DMSO) solution: a. 3 μL of sample + 7 μL of DMSO + 20 μL of DMSO are blended to an initial concentration of 1 mM and mixed uniformly; b. Twelve 5-fold serial dilutions (10 μL of the sample of the previous concentration were sequentially taken and mixed with 40 μL of DMSO) in plate 1, respectively, and uniformly mixed; c. Plate 2 was taken, 45 μL of Buffer was added to each well, and 5 μL of a dilution solution of each concentration of Plate 1 was each taken, added to the corresponding well of Plate 2 (well 1 concentration 100 μM), and mixed uniformly.

Experimental steps:

1. Take 18 μL of MIX, add it to a 384 well plate, and centrifuge at 4500 rpm for 5 minutes.

2. Correspondingly add 2 μL of sample to each well, centrifuge at 25° C. at 4500 rpm for 5 minutes, and mix evenly at 25° C. for 90 minutes on a plate shaker; Data was obtained from a microplate reader and processed with Graphpad Prism 6.0.

NA: data not available

Measurement result of inhibitory activity against MDM2 of the compound of the present invention (IC ₅₀ : nM)

Experiment result:

According to the experimental results in Table 2,

1) All of the compounds of the present invention, such as the compounds prepared in Examples 1 to 180, have an inhibitory action against MDM2, and in particular, all of the S-configuration compounds have a remarkable inhibitory action against MDM2;

2) The inhibitory effect of some compounds of the present invention on MDM2 is superior to that of the positive control compound HDM201, for example, Examples 2, 11, 14, 15, 18, 21, 22, 29, 42, 44, 45, 48 , 49, 52, 53, 61, 62, 63, 66, 67, 69, 70, 72, 73, 74, 75, 77, 78, 79, 81, 82, 90, 92, 95, 96, 98, 102 , 103, 110, 111, 112, 113, 115, 126, 128, 131, 133, 135, 137, 138, 139, 140, 142, 143, 148, 150, 152, 153, 154, 155, 163, 164 , 166, 170, 173, 175, 176 showed that all of the S-configuration compounds were superior to the positive control compound HDM201.

Test Example 2 Measurement of inhibition of the proliferation of the human osteosarcoma cell line SJSA-1 by the MDM2 inhibitor according to the present invention (test subject is the same as Test Example 1)

2.1 Experimental materials: human osteosarcoma cell line SJSA-1 (Nanjing Kebai Biotechnology Co., Ltd.), DAPI (5mg/mL, Beyotime, c1002), 4% paraformaldehyde (Ding Guo Biotech., AR-0211), black transparent Bottom 96 well plate (PE, 6005182), In Cell Analyzer 2200 (GE Healthcare).

2.2 Experiment preparation:

2.2.1 Preparation of human osteosarcoma cell line SJSA-1 culture medium: RPMI1640 + 10% FBS + 1% penicillin / streptomycin

2.2.2 Preparation of test compound solution:

a. Each solution of the test compound at a constant concentration was taken, and diluted with a compound solution having a final concentration of 20 μM in a culture medium.

b. 200 μL of culture medium containing 0.2% DMSO (dimethyl sulfoxide) was added to H2 to H10 of a 96-well plate; 300 μl of the above solution was added to H1.

c. Take 100 μL from well H1, add to H2, and mix uniformly, then take 100 μL and add to H3, and then dilute to H9 sequentially; A solution of the test compound diluted 3 times serially was obtained.

2.3 Experimental process:

2.3.1 SJSA-1 cells were seeded at 4000 cells/100 μl/well, respectively, in a 96-well cell plate with a black transparent bottom, and cultured overnight at 37°C;

2.3.2 Each of the samples was added to the culture plate inoculated with cells at 100 μL/well, tapped to mix evenly, and incubated at 37°C for 72 hours;

2.3.3 Fixation: Take out the cell plate, remove the culture medium, add 50 μL of 4% paraformaldehyde to each well and fix for 10 minutes;

2.3.4 Add 50 μl 0.1M glycine and neutralize for 10 minutes;

2.3.5 Wash twice with 1ХPBS (phosphate buffer pH 7.2);

2.3.6 Permeabilization: 50 μL of 0.2% TritonX-100 (Triton) was added to each well and permeabilized at room temperature for 10 minutes;

2.3.7 Wash twice with 1ХPBS (phosphate buffer pH 7.2);

2.3.8 5 mg/mL DAPI stock solution was diluted 1:5000 (final concentration 1 μg/ml), and staining was performed at room temperature for 20 minutes;

2.3.9 Wash 3 times with 1ХPBS (phosphate buffer pH 7.2);

2.3.10 Scanning and analysis were performed with an In cell analyzer.

2.4 Data processing:

The inhibition rate at each concentration point of each compound was calculated by the following formula, and curve fitting was performed with GraphPad Prism 6.0 software to obtain an IC ₅₀ value.

NA: data not available

Inhibitory activity of the compounds of the present invention on the proliferation of human osteosarcoma cell line SJSA-1

Experiment result:

According to the experimental results in Table 3 above,

1) The compounds of the present invention, such as the compounds prepared in Examples 1 to 180, have an inhibitory effect on the human osteosarcoma cell line SJSA-1, and in particular, the S sequence compound has a remarkable inhibitory effect on the human osteosarcoma cell line SJSA-1. Have;

2) The inhibitory effect of some compounds of the present invention on the human osteosarcoma cell line SJSA-1 is superior to that of the positive control compound HDM201, for example, Examples 2, 4, 6, 9, 11, 12, 13, 15, 22, 23, 24, 25, 32, 33, 42, 45, 49, 61, 69, 72, 74, 75, 78, 82, 83, 86, 89, 91, 92, 96, 98, 99, 101, 102, 103, 106, 108, 110, 113, 114, 115, 119, 121, 126, 127, 131, 137, 138, 139, 141, 143, 145, 146, 153, 154, 155, 157, 159, 162, The inhibitory effects of the S sequence compounds of 164, 166, 172, and 176 on the human osteosarcoma cell line SJSA-1 were all superior to those of the positive control compound HDM201.

Test Example 3 Measurement of the mouse pharmacokinetics of the MDM2 inhibitor according to the present invention

3.1 Experiment summary

ICR mice were used as test animals, and the drug concentration in plasma at different time points was measured by LC/MS/MS method after intravenous injection and intragastric administration of a representative compound to the mouse, and the compound of the present invention in the mouse body The pharmacokinetic behavior was studied and its pharmacokinetic characteristics were evaluated.

3.2 Experimental plan

3.2.1 Test drug:

Some compounds prepared in Examples 1 to 180 of the present invention;

Control drug HDM201 prepared according to the method disclosed in patent CN104203952A.

3.2.2 Test animals:

Healthy adult ICR mice, males, 6 to 9 weeks old, weight 20 to 30 g, were purchased from Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd., and the animal production license number is SCXK(HU)2013-0016.

3.2.3 Preparation of test drug

Intragastric or intravenous administration: Appropriate amount of sample is weighed and dissolved in 5% DMSO + 40% PEG400 + 55% (10% HP-β-CD in Saline) to prepare 0.5 mg/ml solution, intragastric or It was administered intravenously.

3.2.4 Administration of the test drug

Intravenous administration: Each test compound was administered intravenously after fasting 3 male ICR mice overnight, the dosage was 2 mg/kg, and the dosage volume was 1 mL/kg.

Intragastric administration: Each test compound was administered intragastrically after fasting 3 male ICR mice overnight, and the dose was 5mg/kg and the dose volume was 5mL/kg.

3.2.3 Preparation of test drug

Intragastric or intravenous administration: Appropriate amount of sample is weighed and dissolved in 5% DMSO + 40% PEG400 + 55% (10% HP-β-CD in Saline) to prepare 0.5 mg/ml solution, intragastric or It was administered intravenously.

3.2.4 Administration of the test drug

Intravenous administration: Each test compound was administered intravenously after fasting 3 male ICR mice overnight, the dosage was 2 mg/kg, and the dosage volume was 1 mL/kg.

Intragastric administration: Each test compound was administered intragastrically after fasting 3 male ICR mice overnight, and the dose was 5mg/kg and the dose volume was 5mL/kg.

3.3 Experimental operation

Before and after administration of 0.083h, 0.167h, 0.25h, 0.33h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration, about 0.2 mL of blood was collected by jugular vein puncture, and coagulation was prevented with sodium heparin. , After being collected, it was left on ice, and plasma was separated by centrifugation (centrifugation condition: 8000 rpm, 6 minutes, 4°C. The collected plasma was stored at -80°C before analysis, and plasma samples were performed by LC-MS/MS. Was analyzed, the sample was pretreated by the protein precipitation method, and the linear range of the sample analysis was 1 to 2000 ng/ml, the lowest quantification limit was 1 ng/mL. The following pharmacokinetic parameters were determined using WinNonlin (Pharsight, USA). Calculated: area under the curve AUC _(0-t) , area under the curve AUC _(0-Δ , half _- life t _1/2 , retention time MRT _(0-Δ , blood drug concentration C _max , blood drug concentration peak arrival time T _max) , Bioavailability F, apparent volume of distribution Vz, clearance CL.

3.4 Pharmacokinetic data results

Pharmacokinetic parameters after intravenous and oral administration of HDM201 to ICR mice

Pharmacokinetic parameters after intravenous and oral administration of Compound S-1 to ICR mice

Pharmacokinetic parameters after intravenous and oral administration of Compound S-2 to ICR mice

Pharmacokinetic parameters after intravenous and oral administration of Compound S-9 to ICR mice

Pharmacokinetic parameters after intravenous and oral administration of Compound S-11 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-23 to ICR mice

Pharmacokinetic parameters after intravenous and oral administration of S-32 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-44 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-45 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-61 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-69 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-72 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-96 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-98 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-103 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-115 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-121 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-131 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-133 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-134 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-135 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-137 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-138 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-140 to ICR mice

Some pharmacokinetic parameters after intravenous and oral administration of S-159 to ICR mice

Experimental Results : According to the experimental results in Tables 4 to 28, the bioavailability of HDM201 after oral gastric administration at a dose of 5mg/kg is 78.76%, and AUC _0-t is 1126.24h*ng/mL; The AUC _0-t of the representative compound S-1 of the present invention after oral administration at a dose of 5 mg/kg is 1336.16h*ng/mL, and the half-life is 1.64hr, which is superior to the corresponding parameter of HDM201; The bioavailability of compound S-2 is 101.81%, the AUC _0-t is 3728.38h*ng/mL, the half-life is 1.59hr, which is superior to the corresponding parameter of HDM201; The AUC _0-t of compound S-9 is 7329.34h*ng/mL, which is better than the corresponding parameter of HDM201; The bioavailability of compound S-11 is 102.51%, AUC _0-t is 9374.58h*ng/mL, and the half-life is 1.69hr, which is superior to the corresponding parameter of HDM201; The AUC _0-t of compound S-23 is 8011.09h*ng/mL, which is better than the corresponding parameter of HDM201; The AUC _0-t of compound S-32 is 8393.45h*ng/mL, and the half-life is 2.16hr, which is better than the corresponding parameter of HDM201; The bioavailability of compound S-44 is 94.43%, the AUC _0-t is 6451.26h*ng/mL, and the half-life is 2.00hr, which is superior to the corresponding parameter of HDM201; The bioavailability of compound S-45 is 107.31%, the AUC _0-t is 5124.78h*ng/mL, and the half-life is 1.86hr, which is superior to the corresponding parameter of HDM201; The AUC _0-t of compound S-61 is 3528.43h*ng/mL, and the half-life is 3.09hr, which is better than the corresponding parameter of HDM201; The AUC _0-t of compound S-69 is 87014.02h*ng/mL, and the half-life is 2.18hr, which is better than the corresponding parameter of HDM201; The bioavailability of compound S-72 is 107.30%, AUC _0-t is 34074.52h*ng/mL, and the half-life is 1.72hr, which is superior to the corresponding parameter of HDM201; The AUC _0-t of compound S-96 is 8777.27h*ng/mL, and the half-life is 2.11hr, which is better than the corresponding parameter of HDM201; The bioavailability of compound S-98 is 104.66%, the AUC _0-t is 26227.82h*ng/mL, and the half-life is 2.24hr, which is superior to the corresponding parameter of HDM201; The AUC _0-t of compound S-103 is 14639.49h*ng/mL, and the half-life is 1.93hr, which is better than the corresponding parameter of HDM201; The AUC _0-t of compound S-115 is 2998.75h*ng/mL, which is better than the corresponding parameter of HDM201; The AUC _0-t of compound S-121 is 41299.09h*ng/mL, and the half-life is 3.19hr, which is better than the corresponding parameter of HDM201; The AUC _0-t of compound S-131 is 5495.23h*ng/mL, and the half-life is 1.26hr, which is significantly better than the corresponding parameter of HDM201; The AUC _0-t of compound S-133 is 5437.04h*ng/mL, which is better than the corresponding parameter of HDM201; The AUC _0-t of compound S-134 is 7488.67h*ng/mL, and the half-life is 1.45hr, which is better than the corresponding parameter of HDM201; The AUC _0-t of compound S-135 is 8603.42h*ng/mL, which is better than the corresponding parameter of HDM201; The AUC _0-t of compound S-137 is 15422.45h*ng/mL, and the half-life is 1.84hr, which is better than the corresponding parameter of HDM201; The AUC _0-t of compound S-138 is 7690.15h*ng/mL, and the half-life is 2.72hr, which is better than the corresponding parameter of HDM201; The AUC _0-t of compound S-140 is 24174.92h*ng/mL, and the half-life is 2.04hr, which is better than the corresponding parameter of HDM201; The AUC _0-t of compound S-159 is 5495.23h*ng/mL, indicating that it is superior to the corresponding parameter of HDM201.

The basic principles, main features, and advantages of the present invention have been described above. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the description of the embodiments and the specification is only for explaining the principles of the present invention, and the present invention is not departing from the spirit and scope of the invention. It is obvious to those skilled in the art that various changes and improvements can be made to the invention, and all of these changes and improvements fall within the scope of protection of the present invention. The scope of protection of the present invention is determined by the appended claims and their equivalents.

Claims (17)

Compounds of formula I; Or stereoisomers, enantiomers, diastereomers, racemates, mesomers, cis/trans isomers, tautomers, isotopic variants of the compounds of formula I, or any combination thereof; Or a pharmaceutical salt, solvate of the compound of Formula I, its stereoisomer, enantiomer, diastereomer, racemate, mesomer, cis/trans isomer, tautomer, isotopic variant, or any combination thereof , Hydrates, polymorphs or prodrugs; Or a compound that is a hydrate of the pharmaceutical salt:

(I)
Here, R ₁ is straight or branched chain alkyl or cycloalkyl having 1 to 5 carbon atoms, or

Is selected from;
R ₂ is selected from H, (C ₁ -C ₆ alkyl), wherein the alkyl is optionally substituted with 0 to 3 substituents, wherein the 0 to 3 substituents are independently alkoxy having 1 to 4 carbon atoms , Hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methane Selected from sulfonyl;
R ₃ is selected from unsubstituted or 5- or 6-membered aromatic rings or aromatic heterocycles substituted with 1 to 3 substituents, wherein 1 to 3 substituents are independently H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl, -O-(C ₃ -C ₆ )cycloalkyl, -S-(C ₁ -C ₆ )alkyl, halogen, halogenated Alkyl, halogenated alkoxy, hydroxyalkoxy, -CN, -C(O)NR ₉ R ₁₀ , -C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , methyl-imidazolyl-, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C( O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ ,- CH ₂ NR ₉ R ₁₀ , -C(O)O-(C ₁ -C ₄ )alkyl, -CH ₂ CN, tetrahydropyrrol-1-yl, azetidin-1-yl, or one or more -OH or Azetidin-1-yl substituted simultaneously with -CH ₃ and -OH; Here, the alkyl or cycloalkyl is optionally 0 to 3 independently having 1 to 4 carbon atoms alkoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or substituted with a substituent selected from methanesulfonyl; Preferably, R ₃ is selected from unsubstituted or 5- or 6-membered aromatic rings or aromatic heterocycles substituted with 1 to 3 substituents, wherein 1 to 3 substituents are independently H, (C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, halogen, halogenated alkyl, halogenated alkoxy, -CN, -C(O)NR ₉ R ₁₀ ,- C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , methyl-imida Zolyl-, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl,- N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)O-(C ₁ -C ₄ )alkyl, -CH ₂ CN, azetidin-1-yl, or azetidin-1-yl substituted simultaneously with one or more -OH or -CH ₃ and -OH; Here, the alkyl is optionally 0 to 3 independently alkoxy having 1 to 4 carbon atoms, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ ) substituted with a substituent selected from alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;
Or, the R ₃ is

or

Is selected from;
R ₅ is selected from unsubstituted or 5- or 6-membered aromatic rings or aromatic heterocycles substituted with 1 to 3 substituents, wherein 1 to 3 substituents are independently H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl, -O-(C ₃ -C ₆ )cycloalkyl, -S-(C ₁ -C ₆ )alkyl, halogen, halogenated Alkyl, halogenated alkoxy, hydroxyalkoxy, -CN, -C(O)NR ₉ R ₁₀ , -C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , methyl-imidazolyl-, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C( O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ ,- CH ₂ NR ₉ R ₁₀ , -C(O)OCH ₃ , -CH ₂ CN, tetrahydropyrrol-1-yl, azetidin-1-yl, or at least one -OH or -CH ₃ and -OH simultaneously Selected from substituted azetidin-1-yl; Here, the alkyl or cycloalkyl is optionally 0 to 3 independently having 1 to 4 carbon atoms alkoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or substituted with a substituent selected from methanesulfonyl; Preferably, R ₅ is selected from unsubstituted or 5- or 6-membered aromatic rings or aromatic heterocycles substituted with 1 to 3 substituents, wherein 1 to 3 substituents are independently H, (C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, halogen, halogenated alkyl, halogenated alkoxy, -CN, -C(O)NR ₉ R ₁₀ ,- C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ CN , Methyl-imidazolyl-, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)OCH ₃ , -CH ₂ CN, azetidin-1-yl, or azetidin-1-yl substituted simultaneously with one or more -OH or -CH ₃ and -OH; Here, the alkyl is optionally 0 to 3 independently alkoxy having 1 to 4 carbon atoms, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ ) substituted with a substituent selected from alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;
Or the R ₅ is

or

Is selected from;
R ₆ is selected from halogen, methyl halide, methyl or cyano;
R ₇ is selected from H, (C ₁ -C ₆ )alkyl, or halogen; Here, the alkyl is optionally 0 to 3 independently alkoxy having 1 to 4 carbon atoms, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ ) substituted with a substituent selected from alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;
here,
R ₈ is selected from -OH, -OCH ₃ , -NH ₂ , -NHMe, -NMe ₂ , -NHCOMe, -NHCOH or methanesulfonyl;
R ₉ is selected from H or alkyl having 1 to 4 carbon atoms;
R ₁₀ is selected from H or (C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independently of 1 to 4 carbon atoms alkoxy, hydroxy, sulfhydryl, halogen, -C Substituted with a substituent selected from (O)OH, -C(O)O-(C ₁ -C ₄ )alkyl or methanesulfonyl;
R ₁₁ is selected from -OCH ₃ , -CH ₂ CH ₃ , -OH, methoxy halide or H;
R ₁₂ is selected from H or (C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independently of 1 to 4 carbon atoms alkoxy, hydroxy, sulfhydryl, halogen, -C Substituted with a substituent selected from (O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;
R ₁₃ is selected from halogen or alkyl having 1 to 4 carbon atoms;
R ₁₄ is selected from H or (C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independently of 1 to 4 carbon atoms alkoxy, hydroxy, sulfhydryl, halogen, -C Substituted with a substituent selected from (O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;
R ₁₅ is selected from NH ₂ , -C(O)OH, -NH(C(O)-CH ₃ ) or -C(O)-NH(CH ₃ );
R ₁₆ is selected from H, (C ₁ -C ₆ )alkyl or halogen; Here, the alkyl is optionally 0 to 3 independently alkoxy having 1 to 4 carbon atoms, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ ) substituted with a substituent selected from alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;
R ₁₇ is -C(O)-NR ₉ (R ₁₀ ), (C ₁ -C ₆ )alkyl, -C(O)(C ₁ -C ₆ )alkyl, -C(O)O(C ₁ -C ₆ ) is selected from alkyl; Here, the alkyl is optionally 0 to 3 independently alkoxy having 1 to 4 carbon atoms, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ ) substituted with a substituent selected from alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl; And X ₁ is selected from oxygen or sulfur; Y, X ₂ , V and W are each independently selected from carbon or nitrogen; When Y is carbon, R ₄ is H, hydroxy, -O-(C ₁ -C ₆ )alkyl, -CN, halogen, (C ₁ -C ₆ )alkyl, -C(O)OH, -CH ₂ C(O)OH, -CH ₂ C(O)NR ₉ R ₁₀ or -C(O)O-(C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independently Substituted with a substituent selected from alkoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl or methanesulfonyl having 1 to 4 carbon atoms . The method of claim 1,
The straight or branched chain alkyl or cycloalkyl having 1 to 5 carbon atoms in R _{1 is selected} from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, cyclobutyl or cyclopentyl;
The alkoxy in R ₂ is selected from methoxy or ethoxy;
The alkyl halide in R ₃ is methyl halide, preferably -CF ₃ , -CHF ₂ or -CH ₂ F; Said halogenated alkoxy is _{-OCF 3, -OCHF 2, -OCH 2} F, -OCH 2 CF 3, -OCH 2 CHF 2 , or -OCH ₂ CH ₂ are selected from F, preferably -OCF _3, -OCHF _2, Or -OCH ₂ F; And/or the alkoxy is selected from methoxy or ethoxy;
The alkyl halide in R ₅ is methyl halide, preferably -CF ₃ , -CHF ₂ or -CH ₂ F; Said halogenated alkoxy is _{-OCF 3, -OCHF 2, -OCH 2} F, -OCH 2 CF 3, -OCH 2 CHF 2 , or -OCH ₂ CH ₂ are selected from F, preferably -OCF _3, -OCHF _2, Or -OCH ₂ F; And/or the alkoxy is selected from methoxy or ethoxy;
The halogen in R ₆ is selected from chlorine, fluorine or bromine, and/or the methyl halide is selected from trifluoromethyl, difluoromethyl or monofluoromethyl;
The alkoxy in R ₇ is selected from methoxy or ethoxy;
The alkyl in R ₉ is selected from methyl or ethyl;
The alkoxy in R ₁₀ is selected from methoxy or ethoxy;
The halogenated methoxyl in R ₁₁ is selected from -OCF ₃ , -OCHF ₂ or -OCH ₂ F;
The alkoxy in R ₁₂ is selected from methoxy or ethoxy;
The alkyl in R ₁₃ is selected from methyl or ethyl;
The alkoxy in R ₁₄ is selected from methoxy or ethoxy;
The alkoxy in R ₁₆ is selected from methoxy or ethoxy;
The alkoxy in R ₁₇ is selected from methoxy or ethoxy; And/or
In R ₄ , the alkoxy is characterized in that it is selected from methoxy or ethoxy. The method according to claim 1 or 2,
R ₁ is selected from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, cyclobutyl, cyclopentyl, or

or

Is;
R ₂ is selected from H or methyl;
R ₃ is selected from a 6-membered aromatic ring or an aromatic heterocycle substituted with 1 to 3 substituents, and the substituents are independently H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl,- O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, -O-(C ₃ -C ₆ )cycloalkyl, halogen, -CF ₃ , -CHF ₂ , -CH ₂ F _{, -OCF 3, -OCHF 2, -OCH} 2 F, -OCH 2 CF 3, -OCH 2 CHF 2, -OCH 2 CH 2 F, hydroxy-alkoxy, -CN, -C (O) NR 9 R 10, -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ CN, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C( O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ ,- CH ₂ NR ₉ R ₁₀ , -C(O)O-(C ₁ -C ₄ )alkyl, -CH ₂ CN, tetrahydropyrrol-1-yl, wherein the alkyl or cycloalkyl is optionally 0 To 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ Substituted with a substituent selected from R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl; Preferably, R ₃ is selected from a 6-membered aromatic ring or an aromatic heterocycle substituted with 1 to 3 substituents, and the substituents are independently H, (C ₁ -C ₆ )alkyl, -O-(C _1- C ₆ )alkyl, halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -CN, -C(O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ CN, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)O-(C ₁ -C ₄ )alkyl, -CH ₂ CN, wherein the alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulf A substituent selected from hydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl Substituted with; Preferably, R ₃ is selected from 6-membered aromatic rings or aromatic heterocycles substituted with 1 to 3 substituents, and the substituents are independently H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy , ethoxy, isopropoxy, -O- cyclopropyl, hydroxy-ethoxy, _{halogen, -CF 3, -CHF 2, -CH} 2 F, -OCF 3, -OCHF 2, -OCH 2 F, -OCH 2 CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CH ₂ F, -CN, -C(O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ CN, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl , -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)O-(C ₁ -C ₄ ) Selected from alkyl, tetrahydropyrrol-1-yl;
R ₅ is selected from a 6-membered aromatic ring or an aromatic heterocycle substituted with 1 to 3 substituents, and the substituents are preferably independently H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cyclo Alkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, -O-(C ₃ -C ₆ )cycloalkyl, halogen, -CF ₃ , -CHF ₂ ,- _{CH 2 F, -OCF 3, -OCHF} 2, -OCH 2 F, -OCH 2 CF 3, -OCH 2 CHF 2, -OCH 2 CH 2 F, hydroxy-alkoxy, -CN, -C (O) NR 9 R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ CN, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)OCH ₃ , -CH ₂ CN, tetrahydropyrrol-1-yl, wherein the alkyl or cycloalkyl is optionally 0 to 3 independently Methoxy, ethoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ substituted with a substituent selected from R ₁₀ or methanesulfonyl; Preferably, R ₅ is selected from a 6-membered aromatic ring or an aromatic heterocycle substituted with 1 to 3 substituents, and the substituents are preferably independently H, (C ₁ -C ₆ )alkyl, -O-( C ₁ -C ₆ )alkyl, halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -CN, -C(O)NR ₉ R ₁₀ ,- CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ CN, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O )OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl, -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)OCH ₃ , -CH ₂ CN, wherein the alkyl is optionally 0 to 3 independently of methoxy, ethoxy, hydroxy, sulfhydryl, halogen, Substituted with a substituent selected from -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl; Preferably, R ₅ is selected from a 6-membered aromatic ring or an aromatic heterocycle substituted with 1 to 3 substituents, and the substituents are independently H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy , ethoxy, isopropoxy, -O- cyclopropyl, hydroxy-ethoxy, _{halogen, -CF 3, -CHF 2, -CH} 2 F, -OCF 3, -OCHF 2, -OCH 2 F, -OCH 2 CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CH ₂ F, -CN, -C(O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -CH ₂ CN, -CH ₂ C(O)NR ₉ R ₁₀ , -CH ₂ C(O)OH, -C(O)OH, -CH ₂ C(O)O-(C ₁ -C ₄ )alkyl , -N(R ₉ )-C(O)-(C ₁ -C ₄ )alkyl, -NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -C(O)OCH ₃ , tetrahydropyrrole-1- Is selected from work;
R ₆ is selected from chlorine or cyano;
R ₇ is hydrogen;
X ₁ is oxygen;
X ₂ , V and W are all carbon; And/or
Y is nitrogen or carbon; When Y is carbon, R ₄ is H, hydroxy, -O-(C ₁ -C ₆ )alkyl, -C(O)OH, -CH ₂ C(O)OH, -CH ₂ C(O)NR ₉ R ₁₀ or -C(O)O-(C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen , -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or substituted with a substituent selected from methanesulfonyl,
Wherein R ₉ is selected from H, methyl or ethyl;
R ₁₀ is selected from H or (C ₁ -C ₆ )alkyl, wherein said alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen, -C(O) OH, -C(O)O-(C ₁ -C ₄ )alkyl or methanesulfonyl, characterized in that substituted with a substituent selected from. The method according to any one of claims 1 to 3,
Y is carbon or nitrogen; Here, when Y is nitrogen, R ₄ does not exist; When Y is carbon, R ₄ is H, hydroxy, -O-(C ₁ -C ₆ )alkyl, -C(O)OH, -CH ₂ C(O)OH, -CH ₂ C(O)NR ₉ R ₁₀ or -C(O)O-(C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen , -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl;
R ₁ is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl;
R ₂ is H;
R ₃ is a 6-membered aromatic ring or an aromatic heterocycle substituted with 1 to 3 substituents, and the aromatic heterocycle is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring, wherein The substituents are independently H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl,- O- (C ₃ -C ₆₎ cycloalkyl, _{halogen, -CF 3, -CHF 2, -CH} 2 F, -OCF 3, -OCHF 2, -OCH 2 F, -OCH 2 CF 3, -OCH 2 CHF ₂ , -OCH ₂ CH ₂ F, hydroxyalkoxy, -CN, -C(O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -C( O)OH, -CH ₂ NR ₉ R ₁₀ , tetrahydropyrrol-1-yl or -NR ₉ R ₁₀ ; Here, the alkyl or cycloalkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ ) substituted with a substituent selected from alkyl, -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or methanesulfonyl; Preferably, R ₃ is a 6-membered aromatic ring or aromatic hetero ring substituted with 1 to 3 substituents, and the aromatic hetero ring is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, or a pyridazine And the substituent is independently H, (C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, halogen, -CF ₃ ,- _{CHF 2, -CH 2 F, -OCF} 3, -OCHF 2, -OCH 2 F, -CN, -C (O) NR 9 R 10, -CH 2 NR 9 R 10, -CH 2 NR 9 -C ( O)R ₁₀ , -C(O)OH, -CH ₂ NR ₉ R ₁₀ or -NR ₉ R ₁₀ ; Here, the alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl , -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or substituted with a substituent selected from methanesulfonyl; Preferably, R ₃ is selected from a 6-membered aromatic ring or an aromatic hetero ring substituted with 1 to 3 substituents, and the aromatic hetero ring is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, or Is a pyridazine ring, and the substituents are independently H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl, hydroxyethoxy, halogen,- _{CF 3, -CHF 2, -CH 2} F, -OCF 3, -OCHF 2, -OCH 2 F, -OCH 2 CF 3, -OCH 2 CHF 2, -OCH 2 CH 2 F, -CN, -C ( O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -C(O)OH, -CH ₂ NR ₉ R ₁₀ , tetrahydropyrrol-1-yl Or -NR ₉ R ₁₀ ;
R ₅ is a 6-membered aromatic ring or an aromatic hetero ring substituted with 1 to 3 substituents, and the aromatic hetero ring is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring; The substituents are independently H, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, -O- (C ₃ -C ₆₎ cycloalkyl, _{halogen, -CF 3, -CHF 2, -CH} 2 F, -OCF 3, -OCHF 2, -OCH 2 F, -OCH 2 CF 3, -OCH 2 CHF ₂ , -OCH ₂ CH ₂ F, hydroxyalkoxy, -CN, -C(O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -C (O)OH, -CH ₂ NR ₉ R ₁₀ , tetrahydropyrrol-1-yl or -NR ₉ R ₁₀ ; Here, the alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl , -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or substituted with a substituent selected from methanesulfonyl; Preferably, R ₅ is a 6-membered aromatic ring or aromatic heterocycle substituted with 1 to 3 substituents, and the aromatic heterocycle is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring. Is; The substituents are independently H, (C ₁ -C ₆ )alkyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, halogen, -CF ₃ , -CHF ₂ , _{-CH 2 F, -OCF 3, -OCHF} 2, -OCH 2 F, -CN, -C (O) NR 9 R 10, -CH 2 NR 9 R 10, -CH 2 NR 9 -C (O) R ₁₀ , -C(O)OH, -CH ₂ NR ₉ R ₁₀ , or -NR ₉ R ₁₀ ; Here, the alkyl is optionally 0 to 3 independently methoxy, ethoxy, hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl , -C(O)NR ₉ R ₁₀ , -NR ₉ R ₁₀ or substituted with a substituent selected from methanesulfonyl; Preferably, R ₅ is selected from a 6-membered aromatic ring or an aromatic hetero ring substituted with 1 to 3 substituents, and the aromatic hetero ring is preferably a pyridine ring, a pyridone ring, a pyrimidine ring, a pyrazine ring, or Is a pyridazine ring, and the substituents are independently H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -O-cyclopropyl, hydroxyethoxy, halogen,- _{CF 3, -CHF 2, -CH 2} F, -OCF 3, -OCHF 2, -OCH 2 F, -OCH 2 CF 3, -OCH 2 CHF 2, -OCH 2 CH 2 F, -CN, -C ( O)NR ₉ R ₁₀ , -CH ₂ NR ₉ R ₁₀ , -CH ₂ NR ₉ -C(O)R ₁₀ , -C(O)OH, -CH ₂ NR ₉ R ₁₀ , tetrahydropyrrol-1-yl Or -NR ₉ R ₁₀ ;
R ₆ is chlorine;
R ₇ is hydrogen;
X ₁ is oxygen; And/or
X ₂ , V and W are all carbon;
Wherein R ₉ is selected from H, methyl or ethyl, R ₁₀ is selected from H, (C ₁ -C ₆ )alkyl, wherein the alkyl is optionally 0 to 3 independently methoxy, ethoxy, Substituted with a substituent selected from hydroxy, sulfhydryl, halogen, -C(O)OH, -C(O)O-(C ₁ -C ₄ )alkyl or methanesulfonyl; R ₁₀ is preferably H, methyl, ethyl or 1-hydroxyethyl, more preferably H, methyl or ethyl. The method according to any one of claims 1 to 4,
The compound of formula I is a compound, characterized in that one selected from the following structures:

The method according to any one of claims 1 to 5,
The compound is characterized in that the S configuration, the compound. If Y is N,

(1) synthesizing compound 3 by substituting and rearranging compound 1 and compound 2;
(2) cyclization reaction of compound 3 and compound 4 to form an imidazole ring to obtain compound 5;
(3) brominating compound 5 with NBS to obtain compound 6;
(4) obtaining compound 8 by performing low-temperature lithiation of compound 6 and compound 7 with LDA;
(5) ammonia decomposition reaction of compound 8 and compound 9 to obtain compound 10;
(6) acidifying and dehydrating compound 10 to obtain compound 11;
(7) a step of obtaining product 12 by reacting compound 11 with aryl or heteroaryl borate or boronic acid by Suzuki coupling;
Here, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , X ₁ , X ₂ , V, W are as defined in any one of claims 1 to 4 , A method for producing the compound of any one of claims 1 to 6. If Y is C,

(1) synthesizing compound 3 by substitution reaction of compound 1 and compound 2;
(2) brominating compound 3 with NBS to obtain compound 4;
(3) obtaining compound 6 by lithiation of compound 4 and compound 5 with LDA at low temperature;
(4) obtaining compound 8 by subjecting compound 6 and compound 7 to ammonia decomposition reaction;
(5) acidifying and dehydrating compound 8 to obtain compound 9;
(6) obtaining product 11 by reacting compound 9 with aryl or heteroaryl boronic acid by Suzuki coupling;
Here, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , X ₁ , X ₂ , V, W are as defined in any one of claims 1 to 4, and ; Preferably, X ₁ is O, characterized in that, the method for producing the compound of any one of claims 1 to 6. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 6 as an active ingredient. In the manufacture of a drug for the treatment of diseases based on cell cycle dysregulation,
The disease is preferably a tumor or nephritis disease; The use of a compound according to any one of claims 1 to 6 or a composition of claim 9, more preferably a disorder or disease mediated by MDM2 and/or MDM4 activity. The method of claim 10,
Diseases based on the cell cycle dysregulation include proliferative disorders or diseases,
Preferably, the disease based on cell cycle dysregulation includes cancer or tumor disease; The tumor diseases include benign or malignant tumors;
More preferably,
The tumor diseases include soft tissue sarcoma or sarcoma, leukemia or bone cancer; Preferably, the sarcoma is liposarcoma or rhabdomyosarcoma; The leukemia is acute myelogenous leukemia, chronic myelogenous leukemia or B-cell chronic lymphocytic leukemia; The bone cancer is osteosarcoma;
The cancer is brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer or thyroid cancer, glioblastoma, meningioma, glioma, mesothelioma, multiple myeloma, Including gastrointestinal cancer; In particular colon cancer or colorectal adenoma, head and neck tumor, melanoma, prostatic hyperplasia, tumorigenesis, tumorigenesis of epithelial features, leukemia, lymphoma, and other organ metastases and viral infections;
More preferably, the leukemia is acute myelogenous leukemia or B-cell chronic lymphocytic leukemia; The lymphoma is a lymphoma of B- or T-cell origin; The viral infection is herpes, papilloma, HIV, Kaposi's, viral hepatitis;
Alternatively, the disease based on the cell cycle regulation disorder is an immune system-related disorder or disease, preferably an autoimmune disease or immune disease, chronic inflammatory disease, or skin inflammatory or allergic disease, or other skin inflammatory or allergic disease due to transplantation. Disease, or hyperproliferative disorder;
Preferably, the autoimmune disease or immune disease caused by the transplant is rheumatoid arthritis, graft versus host disease, systemic lupus erythematosus, Sjogren syndrome, multiple sclerosis, Hashimoto's thyroiditis, and multiple myositis;
The chronic inflammatory disease is asthma, osteoarthritis, nephritis, atherosclerosis or Morbus Crohn;
The skin inflammatory or allergic diseases include psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, polymorphic erythema, herpetic dermatitis, sclerosis, vitiligo, allergic vasculitis, urticaria, vesicular pemphigus, pemphigus, acquired blistering epidermis Detachment;
Use, characterized in that the hyperproliferative disorder is Li-Fraumeni syndrome. It comprises administering an effective amount of the compound of any one of claims 1 to 6 or the composition of claim 9 to a subject in need by oral administration or parenteral administration route;
The disease is preferably a tumor or nephritis disease; More preferably, it is a disorder or disease mediated by MDM2 and/or MDM4 activity. A method of treating a disease based on a cell cycle dysregulation disorder. The method of claim 12,
Diseases based on the cell cycle dysregulation include cancer or tumor disease; The tumor diseases include benign or malignant tumors;
Preferably,
The tumor diseases include soft tissue sarcoma or sarcoma, leukemia or bone cancer; Preferably, the sarcoma is liposarcoma or rhabdomyosarcoma; The leukemia is acute myelogenous leukemia, chronic myelogenous leukemia or B-cell chronic lymphocytic leukemia; The bone cancer is osteosarcoma;
The cancer is brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer or thyroid cancer, glioblastoma, meningioma, glioma, mesothelioma, multiple myeloma, Including gastrointestinal cancer; In particular colon cancer or colorectal adenoma, head and neck tumor, melanoma, prostatic hyperplasia, tumorigenesis, tumorigenesis of epithelial features, leukemia, lymphoma, and other organ metastases and viral infections;
More preferably, the leukemia is acute myelogenous leukemia or B-cell chronic lymphocytic leukemia; The lymphoma is a lymphoma of B- or T-cell origin; The viral infection is herpes, papilloma, HIV, Kaposi's, viral hepatitis;
Alternatively, the disease based on the cell cycle regulation disorder is an immune system-related disorder or disease, preferably an autoimmune disease or immune disease, chronic inflammatory disease, or skin inflammatory or allergic disease, or other skin inflammatory or allergic disease due to transplantation. Disease, or hyperproliferative disorder;
Preferably,
The autoimmune diseases or immune diseases caused by the transplant are rheumatoid arthritis, graft versus host disease, systemic lupus erythematosus, Sjogren syndrome, multiple sclerosis, Hashimoto's thyroiditis, and multiple myositis;
The chronic inflammatory disease is asthma, osteoarthritis, nephritis, atherosclerosis or Morbus Crohn;
The skin inflammatory or allergic diseases include psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, polymorphic erythema, herpes dermatitis, scleroderma, vitiligo, allergic vasculitis, urticaria, vesicular pemphigus, pemphigus, acquired vesicular epidermis. Detachment;
The method, characterized in that the hyperproliferative disorder is Li-Fraumeni syndrome. The compound of any one of claims 1 to 6 or the composition of claim 9, which is used as a drug. Used in the treatment of diseases based on cell cycle dysregulation;
The disease is preferably a tumor or nephritis disease; The compound of any one of claims 1 to 6 or the composition of claim 9, characterized in that the disorder or disease is more preferably mediated by MDM2 and/or MDM4 activity. Diseases based on the cell cycle dysregulation include cancer or tumor disease; The tumor diseases include benign or malignant tumors;
Preferably,
The tumor diseases include soft tissue sarcoma or sarcoma, leukemia or bone cancer; Preferably, the sarcoma is liposarcoma or rhabdomyosarcoma; The leukemia is acute myelogenous leukemia, chronic myelogenous leukemia or B-cell chronic lymphocytic leukemia; The bone cancer is osteosarcoma;
The cancer is brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer or thyroid cancer, glioblastoma, meningioma, glioma, mesothelioma, multiple myeloma, Including gastrointestinal cancer; In particular colon cancer or colorectal adenoma, head and neck tumor, melanoma, prostatic hyperplasia, tumorigenesis, tumorigenesis of epithelial features, leukemia, lymphoma, and other organ metastases and viral infections;
More preferably, the leukemia is acute myelogenous leukemia or B-cell chronic lymphocytic leukemia; The lymphoma is a lymphoma of B- or T-cell origin; The viral infection is herpes, papilloma, HIV, Kaposi's, viral hepatitis;
Alternatively, the disease based on the cell cycle regulation disorder is an immune system-related disorder or disease, preferably an autoimmune disease or immune disease, chronic inflammatory disease, or skin inflammatory or allergic disease, or other skin inflammatory or allergic disease due to transplantation. Disease, or hyperproliferative disorder;
Preferably,
The autoimmune diseases or immune diseases caused by the transplant are rheumatoid arthritis, graft versus host disease, systemic lupus erythematosus, Sjogren syndrome, multiple sclerosis, Hashimoto's thyroiditis, and multiple myositis;
The chronic inflammatory disease is asthma, osteoarthritis, nephritis, atherosclerosis or Morbus Crohn;
The skin inflammatory or allergic diseases include psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, polymorphic erythema, herpetic dermatitis, sclerosis, vitiligo, allergic vasculitis, urticaria, vesicular pemphigus, pemphigus, acquired blistering epidermis Detachment;
The compound or composition of claim 15, wherein the hyperproliferative disorder is Li-Fraumeni syndrome. The compound of any one of claims 1 to 6 in combination with one or more therapeutically active agents, preferably in combination with one or more other antiproliferative compounds.